Heterocyclic modulators of the glucocorticoid receptor, AP-1, and/or NF-kB activity and use thereof

ABSTRACT

The invention relates to a class of novel non-steroidal compounds which are useful in treating diseases associated with modulation of the glucocorticoid receptor, AP-1, and/or NF-κB activity including obesity, diabetes, inflammatory and immune diseases, and have the structure of formula (I)  
                 
 
or stereoisomers or prodrugs or solvates or pharmaceutically acceptable salts thereof, wherein Z, R, R 4 , R 5 , R a , R b , R c , and R d , are defined herein. Also provided are pharmaceutical compositions and methods of treating obesity, diabetes and inflammatory or immune associated diseases comprising said compounds.

This application claims the benefit of priority from U.S. ProvisionalApplication Ser. No. 60/643,760, filed Jan. 13, 2005, the entirety ofwhich is incorporated by reference herein.

FIELD OF THE INVENTION

The present invention relates to new non-steroidal compounds which aremodulators of the glucocorticoid receptor, AP-1, and/or NF-κB activityand thus are useful in treating diseases such as obesity, diabetes andinflammatory or immune associated diseases, and to a method for usingsuch compounds to treat these and related diseases.

BACKGROUND OF THE INVENTION

The transcription factors NF-κB and AP-1 are involved in regulating theexpression of a number of genes involved in mediating inflammatory andimmune responses. NF-κB regulates the transcription of genes includingTNF-α, IL-1, IL-2, IL-6, adhesion molecules (such as E-selectin) andchemokines (such as Rantes), among others. AP-1 regulates the productionof the cytokines TNF-α, IL-1, IL-2, as well as, matrix metalloproteases.Drug therapies targeting TNF-α, a gene whose expression is regulated byboth NF-κB and AP-1, have been shown to be highly efficacious in severalinflammatory human diseases including rheumatoid arthritis and Crohn'sdisease. Accordingly, NF-κB and AP-1 play key roles in the initiationand perpetuation of inflammatory and immunological disorders. SeeBaldwin, A S, Journal of Clin. Investigation, 107, 3 (2001); Firestein,G. S., and Manning, A. M., Arthritis and Rheumatism, 42, 609 (1999); andPeltz, G., Curr. Opin, in Biotech. 8, 467 (1997).

There are many signaling molecules (kinases and phosphatases) upstreamof AP-1 and NF-κB which are potential therapeutic drug targets. Thekinase JNK plays an essential role in regulating the phosphorylation andsubsequent activation of c-jun, one of the subunits which constitute theAP-1 complex (fos/c-jun). Compounds which inhibit JNK have been shown tobe efficacious in animal models of inflammatory disease. See Manning A Mand Davis R J, Nature Rev. Drug Disc., V. 2, 554 (2003). A kinasecritical to the activation of NF-κB is the IκB kinase (IKK). This kinaseplays a key role in the phosphorylation of IκB. Once IκB isphosphorylated it undergoes degradation leading to the release of NF-κBwhich can translocate into the nucleus and activate the transcription ofthe genes described above. An inhibitor of IKK, BMS-345541, has beenshown to be efficacious in animal models of inflammatory disease. SeeBurke J R., Curr Opin Drug Discov Devel., September;6(5), 720-8, (2003).

In addition to inhibiting signaling cascades involved in the activationof NF-κB and AP-1, the glucocorticoid receptor has been shown to inhibitthe activity of NF-κB and AP-1 via direct physical interactions. Theglucocorticoid receptor (GR) is a member of the nuclear hormone receptorfamily of transcription factors, and a member of the steroid hormonefamily of transcription factors. Affinity labeling of the glucocorticoidreceptor protein allowed the production of antibodies against thereceptor which facilitated cloning the glucocorticoid receptors. Forresults in humans see Weinberger, et al., Science 228, 640-742, (1985);Weinberger, et al., Nature, 318, 670-672 (1986) and for results in ratssee Miesfeld, R., Nature, 312, 779-781, (1985).

Glucocorticoids which interact with GR have been used for over 50 yearsto treat inflammatory diseases. It has been clearly shown thatglucocorticoids exert their anti-inflammatory activity via theinhibition by GR of the transcription factors NF-κB and AP-1. Thisinhibition is termed transrepression. It has been shown that the primarymechanism for inhibition of these transcription factors by GR is via adirect physical interaction. This interaction alters the transcriptionfactor complex and inhibits the ability of NF-κB and AP-1 to stimulatetranscription. See Jonat, C., et al., Cell, 62, 1189 (1990); Yang-Yen,H. F., et al,. Cell, 62, 1205 (1990); Diamond, M. I. et al., Science249, 1266 (1990); and Caldenhoven, E. et al., Mol. Endocrinol., 9, 401(1995). Other mechanisms such as sequestration of co-activators by GRhave also been proposed. See Kamer Y, et al., Cell, 85, 403 (1996); andChakravarti, D. et al., Nature, 383, 99 (1996).

In addition to causing transrepression, the interaction of aglucocorticoid with GR can cause GR to induce transcription of certaingenes. This induction of transcription is termed transactivation.Transactivation requires dimerization of GR and binding to aglucocorticoid response element (GRE).

Recent studies using a transgenic GR dimerization defective mouse whichcannot bind DNA have shown that the transactivation (DNA binding)activities of GR could be separated from the transrepressive (non-DNAbinding) effect of GR. These studies also indicate that many of the sideeffects of glucocorticoid therapy are due to the ability of GR to inducetranscription of various genes involved in metabolism, whereas,transrepression, which does not require DNA binding leads to suppressionof inflammation. See Tuckermann, J. et al., Cell, 93, 531 (1998) andReichardt, H M, EMBO J., 20, 7168 (2001).

Additionally, benzoquinolizinium salts, phenanthrene-based derivativesand benzoperhydroisoindole compounds have been reported in theliterature as useful in the treatment or prevention of neurodegenerativedisorders, inflammatory conditions and cancer, respectively. Forexample, U.S. Pat. Nos. 5,455,248; and 6,291,679; Fields, et al., J Org.Chem. 33(1), 390-395 (1968); Fields and Regan, J. Org. Chem. 36(20),2986-2990 (1971); Fields and Regan, J. Org. Chem. 36(20), 2991-2994(1971); Fields, J. Org. Chem. 36(20), 3002-3005 (1971); Westerman andBradsher, J. Org. Chem. 36(7), 969-970 (1971); Bradsher and Day, J. Het.Chem. 10, 1031-1033 (1973); Fields and Regan, J. Org. Chem. 35(6),1870-1875 (1970); Fields et al., J. Org. Chem. 36(20) (1971), 2995-3001;Fields and Miller, J. Het Chem. 7, 91-97 (1970); Bradsher and Stone, J.Org. Chem. 33(2), 519-523 (1968); Bradsher and Solomons, J. Am. Chem.Soc. 80, 933-934 (1958); Bradsher and Stone, J. Org. Chem. 34(6),1700-1702 (1969); Burnham and Bradsher, J. Org. Chem. 37(3), 355-358(1972); Parham et al., J. Org. Chem. 37(3), 358-362 (1972); Bradsher etal., J. Am. Chem. Soc. 99(8), 2588-2591 (1977); Bradsher et al., J. Org.Chem. 43(5), 822-827 (1978); Westerman and Bradsher, J. Org. Chem.43(15), 3002-3006 (1978); Westerman and Bradsher, J. Org. Chem. 44(5),727-733 (1979); Bradsher et al., J. Org. Chem. 44(8), 1199-1201 (19790;PCT application WO 04/005229; and Hart et al., Tetrahedron Letters 52,4639-4642 (1975). Also, PCT application WO 2004/009017 published Jan.29, 2004 and assigned to Applicant, describes substituted bicyclooctanesuseful in treating diseases such as obesity, diabetes and inflammatoryor immune associated diseases.

Compounds that modulate AP-1 and/or NFκB activity would be useful assuch compounds would be useful in the treatment of inflammatory andimmune diseases and disorders such as osteoarthritis, rheumatoidarthritis, multiple sclerosis, asthma, inflammatory bowel disease,transplant rejection and graft vs. host disease.

Also, with respect to the glucocorticoid receptor pathway, it is knownthat glucocorticoids are potent anti-inflammatory agents, however theirsystemic use is limited by side effects. Compounds that retain theanti-inflammatory efficacy of glucocorticoids while minimizing the sideeffects such as diabetes, osteoporosis and glaucoma would be of greatbenefit to a very large number of patients with inflammatory diseases.

Additionally concerning GR, the art is in need of compounds thatantagonize transactivation. Such compounds may be useful in treatingmetabolic diseases associated with increased levels of glucocorticoid,such as diabetes, osteoporosis and glaucoma.

Additionally concerning GR, the art is in need of compounds that causetransactivation. Such compounds may be useful in treating metabolicdiseases associated with a deficiency in glucocorticoid. Such diseasesinclude Addison's disease.

DESCRIPTION OF THE INVENTION

The present invention relates to new non-steroidal compounds which aremodulators of the glucocorticoid receptor, AP-1, and/or NF-κB activityand thus are useful in treating diseases such as obesity, diabetes andinflammatory or immune associated diseases, and to a method for usingsuch compounds to treat these and related diseases.

In one embodiment, the present invention is directed to novel compoundsof Formula I below:

its stereoisomers thereof, tautomers thereof, or a pharmaceuticallyacceptable salt thereof, wherein

R is hydrogen, NHR⁶, hydroxy, alkyl, alkenyl, alkynyl, alkoxy, aryl,arylalkyl, aryloxy, heteroaryl, cycloheteroalkyl, heteroarylalkyl,cycloheteroalkylalkyl, cycloalkyl, cycloalkylalkyl, cyanoalkyl,aminoalkyl, hydroxyalkyl, aryloxyalkyl, or hydroxyaryl;

R⁴ and R⁵ are independently at each occurence hydroxy, alkoxy, aryloxy,cyano, nitro, NR^(e)R^(f), CHO, —CO₂alkyl, OCONR^(e)R^(f), OCO_(t)R^(e),OCO_(t)-aryl, OCO_(t)-heteroaryl, CONR^(e)R^(f), CH₂NR^(e)R^(f), CO₂H,OCSO_(t)R^(e)R^(f), CSNR^(e)R^(f), NR^(g)CO_(t)R^(i),NR^(g)CONR^(e)R^(f), NR^(g)CSNR^(e)R^(f), NR^(g)SO_(t)R^(i),NR^(g)SO₂R^(i), SO₂NR^(e)R^(f), or NR^(g)SO₂NR^(e)R^(f);

R⁶ is hydrogen, S(O)_(t)R^(h), or C(O)_(t)R^(h);

R^(a) and R^(b) are independently selected from hydrogen, halogen,hydroxy, alkyl, alkenyl, alkynyl, alkoxy, aryl, aryloxy, heteroaryl,cycloheteroalkyl, heteroarylalkyl, cycloheteroalkylalkyl, cyano,heteroarylaminocarboyl, cycloheteroalkylcarbonyl, cyanoalkyl,alkylaminoalkyl, hydroxyalkyl, hydroxyaryl, aryloxyalkyl, alkyloxyalkyl,nitro, NR^(e)R^(f), CHO, CO₂alkyl, CONR^(e)R^(f), CH₂NR^(e)R^(f), CO₂H,CH₂OH, CH₂NR^(e)R^(f), NHCOR^(g), NHCONR^(e)R^(f) and NHSO₂R^(g);

R^(c) and R^(d) are independently selected from hydrogen, alkyl,alkenyl, alkynyl, alkoxy, NR^(e)R^(f), aryl, hydroxy, aryloxy,heteroaryl, cycloheteroalkyl, heteroarylalkyl, cycloheteroalkylalkyl,hydroxyaryl, and aryloxyalkyl;

R^(e) and R^(f) are independently at each occurrence selected fromhydrogen, aryl, alkyl, alkenyl, alkynyl, alkoxy, amino, substitutedamino, alkoxyalkyl, alkylaminoalkyl, dialkylaminoalkyl, heteroaryl,cycloheteroalkyl, heteroarylalkyl, cycloheteroalkylalkyl, cycloalkyl,and cycloalkylalkyl, provided R^(e) and R^(f) are not both alkoxy oramino;

or R^(e) and R^(f) at each occurrence can be taken together with thenitrogen to which they are attached to form a 5-, 6- or 7-memberedheteroaryl or cycloheteroalkyl ring which contains 1, 2 or 3 heteroatoms which can be N, O or S;

R^(g), R^(h) and R^(i) are independently at each occurrence selectedfrom hydrogen, aryl, alkyl, alkenyl, alkynyl, alkoxy, amino, substitutedamino, alkoxyalkyl, alkylaminoalkyl, dialkylaminoalkyl, heteroaryl,cycloheteroalkyl, heteroarylalkyl, cycloheteroalkylalkyl, and cycloalkyland cycloalkylalkyl;

Z is S(O)_(t)NR¹R², CONR¹R² or CH₂NR¹R² wherein R¹ and R² areindependently selected from hydrogen, alkyl, alkenyl, alkynyl, alkoxy,cycloalkyl, cycloalkylalkyl, aryl, heteroaryl, heteroarylalkyl,cycloheteroalkyl, cycloalkenyl, monoalkylaminoalkyl, dialkylaminoalkyl,cycloheteroalkylalkyl, hydroxyaryl, aryloxyalkyl, alkoxyalkyl andhydroxyalkyl;

r and s are independently 0, 1, 2, 3, or 4, provided r+s is ≧1; and

t is 1 or 2;

Preferred compounds include the embodiments described in numberedparagraphs 1-11 (below). Whether or not specifically listed, allpreferred compounds described herein include prodrugs thereof, and asolvate thereof, as well as stereoisomers thereof, tautomers thereof, orpharmaceutically acceptable salts thereof.

1. Compounds within the scope of formula (I), as defined above,including all stereoisomers and tautomers thereof, or a pharmaceuticallyacceptable salt thereof, wherein Z is a heterocycloalkyl, aryl, orheteroaryl ring.

2. Compounds within the scope of formula (I), as defined above, theirstereoisomers thereof, tautomers thereof, or a pharmaceuticallyacceptable salt thereof, where

R is alkyl or NHR⁶;

R^(a) and R^(b) are independently selected from hydrogen, halogen,alkyl, cyano, nitro, amino, formyl, CO₂alkyl, CONR^(e)R^(f) andCH₂NR^(e)R^(f); and

R^(c) and R^(d) are independently hydrogen, hydroxy, or nitro.

3. Compounds within the scope of formula (I), as defined above, havingthe structure of formula (II)

their stereoisomers thereof, tautomers thereof, or a pharmaceuticallyacceptable salt thereof, wherein

R is NH₂, —NHC(O)C₁₋₄alkyl, or C₁₋₄alkyl;

R^(a) and R^(b) are independently selected from H, halogen, CN, NO₂,NH₂, CHO, CO₂ alkyl, CONR^(e)R^(f) and CH₂NR^(g)R^(h);

R^(c) and R^(d) are independently H or OH; and

one of R¹ and R² is heteroaryl.

4. Compounds within the scope of numbered paragraph 3, as defined above,their stereoisomers thereof, or a solvate thereof, or a pharmaceuticallyacceptable salt thereof, wherein R² is selected from:

R^(a) and R^(b) are independently H, C₁₋₄alkyl, Br, Cl, NO₂, CN, CHO, orNH₂;

R^(m) and R^(n) are independently selected from hydrogen, halogen,alkoxy, —CO₂R^(g)—C(O)N(R^(e))(R^(f)), alkyl, aryl, and heteroaryl;

R^(o) is hydrogen or alkyl; and

q is 1 or 2.

5. Compounds within the scope of formula (I), as defined above, theirstereoisomers thereof, or a solvate thereof, or a pharmaceuticallyacceptable salt thereof, wherein R⁴ and R⁵ are independently selectedfrom cyano, nitro, CH₂NH₂, CHO, COOH, CO₂alkyl, OCOR^(e), OCO_(t)R^(f),CONR^(e)R^(f), and NR^(g)CO_(t)R^(i).

6. Compounds within the scope of formula (I), as defined above, havingthe structure:

including all stereoisomers thereof, tautomers thereof, or apharmaceutically acceptable salt thereof, wherein:

R² is selected from

R⁴ and R⁵ are independently selected from cyano, nitro, CH₂NH₂, CHO,COOH, CO₂alkyl, OCOR^(e), OCO_(t)R^(f), CONR^(e)R^(f), andNR^(g)CO_(t)R^(i); and

R^(a) and R^(b) are independently hydrogen, methyl, bromo, chloro,nitro, or cyano.

7. Compounds within the scope of numbered paragraph 6, as defined above,their stereoisomers thereof, tautomers thereof, or a pharmaceuticallyacceptable salt thereof, wherein:

R^(m) is selected from hydrogen, CO₂alkyl, napthyl, quinolinyl, or—C(R⁷)(R⁸)-T wherein the napthyl or quinolinyl group is substituted byone or more substituents selected from the group consisting of hydrogen,amino, hydroxy, C₁₋₄ alkyl, C₁₋₄ alkoxy, perfluoro substituted C₁₋₄alkyl, cyano, nitro and halogen;

R^(n) is hydrogen, bromo, or chloro;

T is a cycloalkyl, cycloalkenyl, heterocycloalkyl, aryl, or heteroarylring where each ring is substituted by 0-4 R⁹ and 0-1 R¹⁰;

R⁷ and R⁸ are independently at each occurrence hydrogen, halogen,hydroxy, alkyl, alkenyl, alkynyl, alkoxy, cyano, nitro, NR^(e)R^(f), orCHO;

or R⁷ and R⁸ combine to form ═O or a double bond, wherein the doublebond is substituted by hydrogen, aryl, alkyl, alkenyl, alkynyl, alkoxy,amino, substituted amino, alkoxyalkyl, alkylaminoalkyl,dialkylaminoalkyl, heteroaryl, cycloheteroalkyl, heteroarylalkyl,cycloheteroalkylalkyl, cycloalkyl, or cycloalkylalkyl; and

R⁹ and R¹⁰ are, independently at each occurrence, hydrogen, halogen,hydroxy, alkyl, alkenyl, alkynyl, alkoxy, aryl, aryloxy, heteroaryl,cycloheteroalkyl, heteroarylalkyl, cycloheteroalkylalkyl, cyano,heteroarylaminocarboyl, cycloheteroalkylcarbonyl, cyanoalkyl,alkylaminoalkyl, hydroxyalkyl, hydroxyaryl, aryloxyalkyl, alkoxyalkyl,nitro, oxo, NR^(e)R^(f), CHO, CO₂alkyl, CONR^(e)R^(f), CH₂NR^(e)R^(f),CO₂H, CH₂OH, CH₂NHC(O)R^(e), NHCOR^(i), NHCONR^(e)R^(f), NHSO_(p)R^(i),—SO₂NR^(e)R^(f), NR^(g)SO₂NR^(e)R^(f), or NR^(g)SO_(p)R^(i);

or R⁹and R¹⁰ located on adjacent atoms can be taken together to form anoptionally substituted cycloalkyl, aryl, heteroaryl, or cycloheteroalkylring.

8. Compounds within the scope of numbered paragraph 7, as defined above,their stereoisomers thereof, tautomers thereof, or a pharmaceuticallyacceptable salt thereof, wherein:

R^(n) is H;

R^(m) is

R⁷ and R⁸ are independently hydrogen, halogen, or hydroxyl; or R⁷ and R⁸combine to form ═O; and

R⁹ is C₁₋₄alkoxy; halogen, pyrimidine, isoxazole, pyrazole, or pyridine,where the C₁₋₄alkoxy; halogen, pyrimidine, isoxazole, pyrazole, orpyridine, groups are substituted by hydrogen, morpholinyl, C₁₋₄alkoxy,or C₁₋₄alkyl.

9. Compounds within the scope of numbered paragraph 7, as defined above,their stereoisomers thereof, tautomers thereof, or a pharmaceuticallyacceptable salt thereof, wherein:

R^(n) is H;

R^(m) is

or CO₂C₁₋₄alkyl; and

R¹⁰ is selected from methyl, CF₃, fluoro, chloro and bromo.

10. Compounds within the scope of numbered paragraph 6, as definedabove, having the structure:

(ii) including stereoisomers of (i) thereof, tautomers of (i) thereof,or a pharmaceutically acceptable salt of (i) thereof.

11. Compounds within the scope of numbered paragraph 10, as definedabove, its stereoisomers thereof, tautomers thereof, or apharmaceutically acceptable salt thereof, wherein R⁴ is selected fromCONH₂, cyano, CH₂NH₂, CO₂CH₃, and COOH.

Aspects of the above-described preferred embodiments, includingindividual (or groups of) variables, may replace related aspects ofother embodiments to form other preferred embodiments of the presentinvention.

In another embodiment of the present invention, there is providedpharmaceutical compositions useful in treating endocrine disorders,rheumatic disorders, collagen diseases, dermatologic disease, allergicdisease, ophthalmic disease, respiratory disease, hematologic disease,gastrointestinal disease, inflammatory disease, autoimmune disease,diabetes, obesity, and neoplastic disease, as well as other uses asdescribed herein, which includes a therapeutically effective amount(depending upon use) of a compound of formula (I) of the invention and apharmaceutically acceptable carrier.

In still another embodiment, the present invention provides a method oftreating endocrine disorders, rheumatic disorders, collagen diseases,dermatologic disease, allergic disease, ophthalmic disease, respiratorydisease, hematologic disease, gastrointestinal disease, inflammatorydisease, autoimmune disease, diabetes, obesity, and neoplastic disease,that is a disease associated with the expression product of a gene whosetranscription is stimulated or repressed by glucocorticoid receptors, ora disease associated with AP-1- and/or NFκB (particularly AP-1-)-inducedtranscription, or a disease associated with AP-1 and/orNFκB—(particularly AP-1-) dependent gene expression, wherein the diseaseis associated with the expression of a gene under the regulatory controlof AP-1 and/or NF-κB (particularly AP-1), including inflammatory andimmune diseases and disorders as described hereinafter, which includesthe step of administering a therapeutically effective amount of acompound of formula (I) of the invention to a patient.

Another embodiment of the present invention involves a method fortreating a disease or disorder associated with the expression product ofa gene whose transcription is stimulated or repressed by glucocorticoidreceptors, or a method of treating a disease or disorder associated withAP-1- and/or NF-κB—(particularly AP-1-) induced transcription, or amethod for treating a disease or disorder associated with AP-1 and/orNF-κB (particularly AP-1) dependent gene expression, wherein the diseaseis associated with the expression of a gene under the regulatory controlof AP-1 and/or NF-κβ (particularly AP-1), such as inflammatory andimmune disorders, cancer and tumor disorders, such as solid tumors,lymphomas and leukemia, and fungal infections such as mycosis fungoides.

The term “disease associated with GR transactivation,” as used herein,refers to a disease associated with the transcription product of a genewhose transcription is transactivated by a GR. Such diseases include,but are not limited to: osteoporosis, diabetes, glaucoma, muscle loss,facial swelling, personality changes, hypertension, obesity, depression,and AIDS, the condition of wound healing, primary or secondaryandrenocortical insufficiency, and Addison's disease.

The term “treat”, “treating”, or “treatment,” in all grammatical forms,as used herein refers to the prevention, reduction, or amelioration,partial or complete alleviation, or cure of a disease, disorder, orcondition, wherein prevention indicates treatment of a person at riskfor developing such a disease, disorder or condition.

The terms “glucocorticoid receptor” and “GR,” as used herein, refereither to a member of the nuclear hormone receptor (“NHR”) family oftranscription factors which bind glucocorticoids and either stimulate orrepress transcription, or to GR-beta. These terms, as used herein, referto glucocorticoid receptor from any source, including but not limitedto: human glucocorticoid receptor as disclosed in Weinberger, et al.Science 228, pp. 640-742 (1985), and in Weinberger, et al. Nature, 318,pp. 670-672 (1986); rat glucocorticoid receptor as disclosed inMiesfeld, R. Nature, 312, pp. 779-781 (1985); mouse glucocortoidreceptor as disclosed in Danielson, M. et al. EMBO J., 5, 2513; sheepglucocorticoid receptor as disclosed in Yang, K., et al. J. Mol.Endocrinol. 8, pp. 173-180 (1992); marmoset glucocortoid receptor asdisclosed in Brandon, D. D., et al, J. Mol. Endocrinol. 7, pp. 89-96(1991); and human GR-beta as disclosed in Hollenberg, S M. et al.Nature, 318, p. 635, 1985, Bamberger, C. M. et al. J. Clin Invest. 95,p. 2435 (1995).

The term, “disease or disorder associated with AP-1 and/or NF-κB” asused herein, refers to a disease associated with the expression productof a gene under the regulatory control of AP-1 and/or NF-κB. Suchdiseases include, but are not limited to: inflammatory and immunediseases and disorders; cancer and tumor disorders, such as solidtumors, lymphomas and leukemia; and fungal infections such as mycosisfungoides.

The term “inflammatory or immune associated diseases or disorders” isused herein to encompass any condition, disease, or disorder that has aninflammatory or immune component, including, but not limited to, each ofthe following conditions: transplant rejection (e.g., kidney, liver,heart, lung, pancreas (e.g., islet cells), bone marrow, cornea, smallbowel, skin allografts, skin homografts (such as employed in burntreatment), heart valve xenografts, serum sickness, and graft vs. hostdisease, autoimmune diseases, such as rheumatoid arthritis, psoriaticarthritis, multiple sclerosis, Type I and Type II diabetes, juvenilediabetes, obesity, asthma, inflammatory bowel disease (such as Crohn'sdisease and ulcerative colitis), pyoderma gangrenum, lupus (systemiclupus erythematosis), myasthenia gravis, psoriasis, dermatitis,dermatomyositis; eczema, seborrhoea, pulmonary inflammation, eyeuveitis, hepatitis, Grave's disease, Hashimoto's thyroiditis, autoimmunethyroiditis, Behcet's or Sjorgen's syndrome (dry eyes/mouth), perniciousor immunohaemolytic anaemia, atherosclerosis, Addison's disease(autoimmune disease of the adrenal glands), idiopathic adrenalinsufficiency, autoimmune polyglandular disease (also known asautoimmune polyglandular syndrome), glomerulonephritis, scleroderma,morphea, lichen planus, viteligo (depigmentation of the skin), alopeciaareata, autoimmune alopecia, autoimmune hypopituatarism, Guillain-Barresyndrome, and alveolitis; T-cell mediated hypersensitivity diseases,including contact hypersensitivity, delayed-type hypersensitivity,contact dermatitis (including that due to poison ivy), uticaria, skinallergies, respiratory allergies (hayfever, allergic rhinitis) andgluten-sensitive enteropathy (Celiac disease); inflammatory diseasessuch as osteoarthritis, acute pancreatitis, chronic pancreatitis, acuterespiratory distress syndrome, Sezary's syndrome and vascular diseaseswhich have an inflammatory and or a proliferatory component such asrestenosis, stenosis and artherosclerosis. Inflammatory or immuneassociated diseases or disorders also includes, but is not limited to:endocrine disorders, rheumatic disorders, collagen diseases,dermatologic disease, allergic disease, ophthalmic disease, respiratorydisease, hematologic disease, gastrointestinal disease, inflammatorydisease, autoimmune disease, congenital adrenal hyperplasia,nonsuppurative thyroiditis, hypercalcemia associated with cancer,juvenile rheumatoid arthritis, Ankylosing spondylitis, acute andsubacute bursitis, acute nonspecific tenosynovitis, acute goutyarthritis, post-traumatic osteoarthritis, synovitis of osteoarthritis,epicondylitis, acute rheumatic carditis, pemphigus, bullous dermatitisherpetiformis, severe erythema multiforme, exfoliative dermatitis,seborrheic dermatitis, seasonal or perennial allergic rhinitis,bronchial asthma, contact dermatitis, atopic dermatitis, drughypersensitivity reactions, allergic conjunctivitis, keratitis, herpeszoster ophthalmicus, iritis and iridocyclitis, chorioretinitis, opticneuritis, symptomatic sarcoidosis, fulminating or disseminated pulmonarytuberculosis chemotherapy, idiopathic thrombocytopenic purpura inadults, secondary thrombocytopenia in adults, acquired (autoimmune)hemolytic anemia, leukemias and lymphomas in adults, acute leukemia ofchildhood, regional enteritis, autoimmune vasculitis, multiplesclerosis, chronic obstructive pulmonary disease, solid organ transplantrejection, sepsis. Preferred treatments include treatment of transplantrejection, rheumatoid arthritis, psoriatic arthritis, multiplesclerosis, Type 1 diabetes, asthma, inflammatory bowel disease, systemiclupus erythematosis, psoriasis and chronic pulmonary disease.

In addition, in accordance with the present invention a method oftreating a disease associated with AP-1-induced and/or NF-κB-inducedtranscription (particularly AP-1-induced transcription) is providedwherein a compound of formula (I) of the invention is administered to apatient at risk of developing the disease in a therapeutically effectiveamount to induce NHR transrepression of the AP-1-induced and/orNF-κB-induced transcription (particularly AP-1-induced transcription),thereby treating the disease.

Other therapeutic agents, such as those described hereafter, may beemployed with the compounds of the invention in the present methods. Inthe methods of the present invention, such other therapeutic agent(s)may be administered prior to, simultaneously with or following theadministration of the compound(s) of the present invention.

In a particular embodiment, the compounds of the present invention areuseful for the treatment of the aforementioned exemplary disordersirrespective of their etiology, for example, for the treatment oftransplant rejection, rheumatoid arthritis, inflammatory bowel disease,and viral infections.

Methods of Preparation

The compounds of the present invention may be synthesized by manymethods available to those skilled in the art of organic chemistry.General synthetic schemes for preparing compounds of the presentinvention are described below. These schemes are illustrative and arenot meant to limit the possible techniques one skilled in the art mayuse to prepare the compounds disclosed herein. Different methods toprepare the compounds of the present invention will be evident to thoseskilled in the art. Additionally, the various steps in the synthesis maybe performed in an alternate sequence in order to give the desiredcompound or compounds. Example compounds are typically prepared asracemic mixtures. Preparation of homochiral examples may be carried outby techniques known to one skilled in the art. For example, homochiralcompounds may be prepared by separation of racemic products by chiralphase preparative HPLC. Alternatively, the example compounds may beprepared by methods known to give enantiomerically enriched products.For example, [4+2] cycloadditions may be carried out withstereocontrolling elements within either reacting component (diene ordienophile). Products are thus obtained as diastereomerically enrichedmixtures which give enantiomerically enriched mixtures after asubsequent step in which the stereocontrolling element (typically achiral auxiliary such as oxazolidinone, menthol ester, pantolactoneester, etc.) is removed.

Compounds of formula I of the invention are prepared as described in theSchemes and examples below. In the scheme the various groups A, B, R₁,R₂, R₃ correspond to those described above.

Compounds of formula 3 are constructed by the cycloaddition of acompound of formula 1 with an unsaturated compound of formula 2 neat orin an appropriate solvent such as xylenes, toluene, nitrobenzene orbenzene, at temperatures ranging from room temperature to 200° C. toform compound of formula 3. It is well known that the cycloaddition maybe facilitated by the use of catalysts such as diethylaluminiumchloride, titanium tetrachloride or boron trifluoride diethyl etherate.The cycloaddition may also be carried out at higher pressures as whenthe reactions are performed in sealed vessels. The recently developedmicrowave technology can be applied to the cycloaddition to facilitatethe formation of the cycloadduct in solvents such as nitrobenzene,toluene, dichlorobenzene and DMF at temperatures ranging from 100 to250° C. in times from 15 minutes to 120 minutes. The compound of formula3 is a mixture of 4 regioisomers, which may be separable by prep HPLC.

A compound of formula 3 is reacted with an amine of formula 4 by one ofthe many methods of amidation well known to those skilled in the art(such as treatment of compound of formula 3 in a suitable solvent suchas acetonitrile with 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimidehydrochloride (EDC), 1-hydroxy-7-azabenzotriazole, triethylamine andamine 4) to provide compound of formula (I) of the invention.

DEFINITION OF TERMS

Unless otherwise indicated, the term “lower alkyl”, “alkyl” or “alk” asemployed herein alone or as part of another group includes both straightand branched chain hydrocarbons, containing 1 to 20 carbons, preferably1 to 10 carbons, more preferably 1 to 8 carbons, in the normal chain,and may optionally include an oxygen or nitrogen in the normal chain.Examples of such chains include methyl, ethyl, propyl, isopropyl, butyl,t-butyl, isobutyl, pentyl, hexyl, isohexyl, heptyl, 4,4-dimethylpentyl,octyl, 2,2,4-trimethylpentyl, nonyl, decyl, undecyl, dodecyl, thevarious branched chain isomers thereof, and the like, as well as suchgroups including 1 to 4 substituents such as halo, (including F, Br, Clor I), CF₃, alkoxy, aryl, aryloxy, aryl(aryl) or diaryl, arylalkyl,arylalkyloxy, alkenyl, cycloalkyl, cycloalkylalkyl, cycloalkylalkyloxy,amino, hydroxy, hydroxyalkyl, acyl, heteroaryl, heteroaryloxy, HO—N═,cycloheteroalkyl, alkyloxycarbonyl, alkoxyoximyl, arylheteroaryl,arylalkoxycarbonyl, heteroarylalkyl, heteroarylalkoxy, aryloxyalkyl,aryloxyaryl, alkylamido, alkanoylamino, hydroxyalkyl(alkyl)aminocarbonyl, arylcarbonylamino, nitro, cyano, thiol, haloalkyl,trihaloalkyl and/or alkylthio and/or any of the substituents for aryl.

When numbers appear in a subscript after the symbol “C”, the subscriptdefines with more specificity the number of carbon atoms that aparticular group may contain. The subscript “0” refers to a bond. Whenthe term “alkyl” is used together with another group, such as in“arylalkyl”, this conjunction defines with more specificity at least oneof the substituents that the alkyl will contain. For example,“arylalkyl” or “(aryl)alkyl” refers to an alkyl group as defined abovewhere at least one of the substituents is an aryl, such as benzyl. Also,the term aryl(C₀₋₄)alkyl includes a lower alkyl having at least one arylsubstituent and also includes an aryl directly bonded to another group,i.e., aryl(C₀)alkyl.

Unless otherwise indicated, the term “cycloalkyl” as employed hereinalone or as part of another group includes saturated cyclic hydrocarbongroups containing 1 to 3 rings, including monocyclicalkyl, bicyclicalkyland tricyclicalkyl, containing a total of 3 to 20 carbons forming therings, preferably 3 to 10 carbons, forming the ring and which may befused to 1 or 2 aromatic rings (defined below). Accordingly, the term“cycloalkyl” includes groups such as cyclopropyl, cyclobutyl,cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclodecyl andcyclododecyl, cyclohexenyl,

and the like as well as such groups including 1 to 4 substituents suchas halogen, alkyl, alkoxy, hydroxy, aryl, aryloxy, arylalkyl,cycloalkyl, alkylamido, alkanoylamino, oxo, acyl, arylcarbonylamino,amino, nitro, cyano, thiol and/or alkylthio and/or any of thesubstituents for alkyl.

The term “cycloalkenyl” as employed herein alone or as part of anothergroup refers to cyclic hydrocarbons containing 3 to 12 carbons,preferably 5 to 10 carbons and 1 or 2 double bonds. Exemplarycycloalkenyl groups include cyclopentenyl, cyclohexenyl, cycloheptenyl,cyclooctenyl, cyclohexadienyl, and cycloheptadienyl, which may beoptionally substituted as defined for cycloalkyl.

The term “cycloalkylene” as employed herein refers to a “cycloalkyl”group which includes free bonds and thus is a linking group such as

and the like, and may optionally be substituted as defined above for“cycloalkyl”.

The term “alkanoyl” as used herein alone or as part of another grouprefers to alkyl linked to a carbonyl group.

Unless otherwise indicated, the term “lower alkenyl” or “alkenyl” asused herein by itself or as part of another group refers to straight orbranched chain radicals of 2 to 20 carbons, preferably 2 to 12 carbons,and more preferably 1 to 8 carbons in the normal chain, which includeone to six double bonds in the normal chain, and may optionally includean oxygen or nitrogen in the normal chain. Accordingyly, the term “loweralkenyl” or “alkenyl” includes groups such as vinyl, 2-propenyl,3-butenyl, 2-butenyl, 4-pentenyl, 3-pentenyl, 2-hexenyl, 3-hexenyl,2-heptenyl, 3-heptenyl, 4-heptenyl, 3-octenyl, 3-nonenyl, 4-decenyl,3-undecenyl, 4-dodecenyl, 4,8,12-tetradecatrienyl, and the like as wellas such groups including 1 to 4 substituents such as halogen, haloalkyl,alkyl, alkoxy, alkenyl, alkynyl, aryl, arylalkyl, cycloalkyl, amino,hydroxy, heteroaryl, cycloheteroalkyl, alkanoylamino, alkylamido,arylcarbonylamino, nitro, cyano, thiol, alkylthio and/or any of thesubstituents for alkyl set out herein.

Unless otherwise indicated, the term “lower alkynyl” or “alkynyl” asused herein by itself or as part of another group refers to straight orbranched chain radicals of 2 to 20 carbons, preferably 2 to 12 carbonsand more preferably 2 to 8 carbons in the normal chain, which includeone triple bond in the normal chain, and may optionally include anoxygen or nitrogen in the normal chain. Accordingly, the term “loweralkynyl” or “alkynyl” includes groups such as 2-propynyl, 3-butynyl,2-butynyl, 4-pentynyl, 3-pentynyl, 2-hexynyl, 3-hexynyl, 2-heptynyl,3-heptynyl, 4-heptynyl, 3-octynyl, 3-nonynyl, 4-decynyl,3-undecynyl,4-dodecynyl and the like as well as such groups including 1 to 4substituents such as halogen, haloalkyl, alkyl, alkoxy, alkenyl,alkynyl, aryl, arylalkyl, cycloalkyl, amino, heteroaryl,cycloheteroalkyl, hydroxy, alkanoylamino, alkylamido, arylcarbonylamino,nitro, cyano, thiol, and/or alkylthio, and/or any of the substituentsfor alkyl set out herein.

The terms “arylalkenyl” and “arylalkynyl” as used alone or as part ofanother group refer to alkenyl and alkynyl groups as described abovehaving an aryl substituent.

Where alkyl groups as defined above have single bonds for attachment toother groups at two different carbon atoms, they are termed “alkylene”groups and may optionally be substituted as defined above for “alkyl”.

Where alkenyl groups as defined above and alkynyl groups as definedabove, respectively, have single bonds for attachment at two differentcarbon atoms, they are termed “alkenylene groups” and “alkynylenegroups”, respectively, and may optionally be substituted as definedabove for “alkenyl” and “alkynyl”.

(CH₂)_(p) and (CH₂)_(q), includes alkylene, allenyl, alkenylene oralkynylene groups, as defined herein, each of which may optionallyinclude an oxygen or nitrogen in the normal chain, which may optionallyinclude 1, 2, or 3 substituents which include alkyl, alkenyl, halogen,cyano, hydroxy, alkoxy, amino, thioalkyl, keto, C₃-C₆ cycloalkyl,alkylcarbonylamino or alkylcarbonyloxy; the alkyl substituent may be analkylene moiety of 1 to 4 carbons which may be attached to one or twocarbons in the (CH₂)_(p) or (CH₂)_(q) group to form a cycloalkyl grouptherewith.

Examples of (CH₂)_(p), (CH₂)_(q), alkylene, alkenylene and alkynyleneinclude

The term “halogen” or “halo” as used herein alone or as part of anothergroup (e.g. CF₃ is a haloalkyl group) refers to chlorine, bromine,fluorine, and iodine, with chlorine fluorine or bromine being preferred.

The term “metal ion” refers to alkali metal ions such as sodium,potassium or lithium and alkaline earth metal ions such as magnesium andcalcium, as well as zinc and aluminum.

Unless otherwise indicated, the term “aryl”, as employed herein alone oras part of another group refers to monocyclic and bicyclic aromaticgroups containing 6 to 10 carbons in the ring portion (such as phenyl ornaphthyl including 1-naphthyl and 2-naphthyl) and may optionally includeone to three additional rings fused to a carbocyclic ring or aheterocyclic ring (such as aryl, cycloalkyl, heteroaryl orcycloheteroalkyl rings. Accordingly, the term “aryl” includes, forexample

and may be optionally substituted through available carbon atoms with 1,2, or 3 groups selected from hydrogen, halo, haloalkyl, alkyl,haloalkyl, alkoxy, haloalkoxy, alkenyl, trifluoromethyl,trifluoromethoxy, alkynyl, cycloalkyl-alkyl, cycloheteroalkyl,cycloheteroalkylalkyl, aryl, heteroaryl, arylalkyl, aryloxy,aryloxyalkyl, arylalkoxy, alkoxycarbonyl, arylcarbonyl, arylalkenyl,aminocarbonylaryl, arylthio, arylsulfinyl, arylazo, heteroarylalkyl,heteroarylalkenyl, heteroarylheteroaryl, heteroaryloxy, hydroxy, nitro,cyano, amino, substituted amino wherein the amino includes 1 or 2substituents (which are alkyl, aryl or any of the other aryl compoundsmentioned in the definitions), thiol, alkylthio, arylthio,heteroarylthio, arylthioalkyl, alkoxyarylthio, alkylcarbonyl,arylcarbonyl, alkylaminocarbonyl, arylaminocarbonyl, alkoxycarbonyl,aminocarbonyl, alkylcarbonyloxy, arylcarbonyloxy, alkylcarbonylamino,arylcarbonylamino, arylsulfinyl, arylsulfinylalkyl, arylsulfonylamino orarylsulfonaminocarbonyl, carboxy, cycloalkyl, arylalkoxy,aryloxycarbonyl, cycloalkylaminocarbonyl, cycloalkylalkylaminocarbonyl,alkoxycarbonylalkyl, alkoxyalkylaminocarbonyl, heteroarylaminocarbonyl,heteroarylalkylaminocarbonyl, arylalkylaminocarbonyl,N-hydroxyalkyl(N-alkyl)aminocarbonyl, cycloheteroalkylaminocarbonyl,cycloheteroalkylalkylaminocarbonyl, N-aryl(N-alkyl)aminocarbonyl,N-arylalkyl(N-cyanoalkyl)aminocarbonyl, dialkylaminoalkylaminocarbonyl,dialkylaminocarbonyl, alkyl-, arylalkyl- oraryl-cycloheteroalkylaminocarbonyl, N-dialkylaminoalkyl(N-alkyl orN-arylalkyl)aminocarbonyl, N-heteroarylalkyl(N-alkyl)aminocarbonyl,N-arylalkyl(N-alkyl)aminocarbonyl,N-dialkylamino(N-arylalkyl)aminocarbonyl,N-hydroxyalkyl(N-arylalkyl)aminocarbonyl, aminoalkyloxycarbonyl,cycloheteroalkylcarbonyl, N═N═N, alkylsulfonyl, aminosulfonyl,heteroarylaminosulfonyl, and/or any of the substituents for alkyl setout herein.

Unless otherwise indicated, the term “lower alkoxy”, “alkoxy”, “aryloxy”or “aralkoxy” as employed herein alone or as part of another groupincludes any of the above alkyl, aralkyl or aryl groups linked to anoxygen atom.

Unless otherwise indicated, the term “substituted amino” as employedherein alone or as part of another group refers to amino substitutedwith one or two substituents, which may be the same or different, suchas alkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl,cycloheteroalkyl, cycloheteroalkylalkyl, cycloalkyl, cycloalkylalkyl,haloalkyl, hydroxyalkyl, alkoxyalkyl or thioalkyl. These substituentsmay optionally be further substituted with a carboxylic acid and/or anyof the substituents for alkyl as set out above. In addition, the aminosubstituents may be taken together with the nitrogen atom to which theyare attached to form 1-pyrrolidinyl, 1-piperidinyl, 1-azepinyl,4-morpholinyl, 4-thiamorpholinyl, 1-piperazinyl, 4-alkyl-1-piperazinyl,4-arylalkyl-1-piperazinyl, 4-diarylalkyl-1-piperazinyl, 1-pyrrolidinyl,1-piperidinyl, or 1-azepinyl, optionally substituted with alkyl, alkoxy,alkylthio, halo, trifluoromethyl or hydroxy.

Unless otherwise indicated, the term “lower alkylthio”, alkylthio”,“arylthio” or “aralkylthio” as employed herein alone or as part ofanother group includes any of the above alkyl, aralkyl or aryl groupslinked to a sulfur atom.

Unless otherwise indicated, the term “acyl” as employed herein by itselfor part of another group, as defined herein, refers to an organicradical linked to a carbonyl

group; examples of acyl groups include any of the R groups attached to acarbonyl, such as alkanoyl, alkenoyl, aroyl, aralkanoyl, heteroaroyl,cycloalkanoyl, cycloheteroalkanoyl and the like.

Unless otherwise indicated, the term “lower alkylamino”, “alkylamino”,“acylamino”, “arylamino”, or “arylalkylamino” as employed herein aloneor as part of another group includes any of the above alkyl, aryl orarylalkyl acyl groups linked to a nitrogen atom. The term “acylamino”,for example, includes the group —NHC(O)alkyl.

Unless otherwise indicated, the term “cycloheteroalkyl” as used hereinalone or as part of another group refers to a 5-, 6- or 7-memberedsaturated or partially unsaturated ring which includes 1 to 2 heteroatoms such as nitrogen, oxygen and/or sulfur, linked through a carbonatom or a heteroatom, where possible, optionally via the linker(CH₂)_(p) (where p is 0, 1, 2 or 3), such as

and the like. The above groups may include 1 to 4 substituents such asalkyl, halo, oxo and/or any of of the substituents for alkyl or aryl setout herein. In addition, any of the cycloheteroalkyl rings can be fusedto a cycloalkyl, aryl, heteroaryl or cycloheteroalkyl ring.

Unless otherwise indicated, the term “heteroaryl” as used herein aloneor as part of another group refers to a 5-, 6- or 7-membered aromaticring which includes 1, 2, 3 or 4 hetero atoms such as nitrogen, oxygenor sulfur, and such rings fused to an aryl, cycloalkyl, heteroaryl orcycloheteroalkyl ring (e.g. benzothiophenyl, indolyl), and includespossible N-oxides, linked through a carbon atom or a heteroatom, wherepossible, optionally via the linker (CH₂)_(q) (where q is 0, 1, 2 or 3).The heteroaryl group may optionally include 1 to 4 substituents such asany of the substituents for alkyl or aryl set out above. Examples ofheteroaryl groups include the following:

and the like.

The term “cycloheteroalkylalkyl” as used herein alone or as part ofanother group refers to cycloheteroalkyl groups as defined above linkedthrough a C atom or heteroatom to a (CH₂)_(p) chain.

The term “heteroarylalkyl” or “heteroarylalkenyl” as used herein aloneor as part of another group refers to a heteroaryl group as definedabove linked through a C atom or heteroatom to a —(CH₂)_(q)— chain,alkylene or alkenylene as defined above.

The term “polyhaloalkyl” as used herein refers to an “alkyl” group asdefined above which includes from 2 to 9, preferably from 2 to 5, halosubstituents, such as F or Cl, preferably F, such as CF₃CH₂, CF₃ orCF₃CF₂CH₂.

The term “polyhaloalkyloxy” as used herein refers to an “alkoxy” or“alkyloxy” group as defined above which includes from 2 to 9, preferablyfrom 2 to 5, halo substituents, such as F or Cl, preferably F, such asCF₃CH₂O, CF₃O or CF₃CF₂CH₂O.

The term ‘homochiral’ refers to a compound of high enantiomeric purity(greater than 95% enantiomeric excess). The term ‘homochiral’ does notdefine or imply the absolute stereochemical assignment of the compoundto which it refers.

The term “prodrug” denotes a compound which, upon administration to asubject, undergoes chemical conversion by metabolic or chemicalprocesses to yield a compound of the formula (I), and/or a salt and/orsolvate thereof. For example, compounds containing a carboxy group canform physiologically hydrolyzable esters which serve as prodrugs bybeing hydrolyzed in the body to yield formula (I) compounds per se. Suchprodrugs are preferably administered orally since hydrolysis in manyinstances occurs principally under the influence of the digestiveenzymes. Parenteral administration may be used where the ester per se isactive, or in those instances where hydrolysis occurs in the blood.Examples of physiologically hydrolyzable esters of compounds of formula(I) include C₁₋₆alkylbenzyl, 4-methoxybenzyl, indanyl, phthalyl,methoxymethyl, C₁₋₆alkanoyloxy-C₁₋₆alkyl, e.g. acetoxymethyl,pivaloyloxymethyl or propionyloxymethyl,C₁₋₆alkoxycarbonyloxy-C₁₋₆alkyl, e.g. methoxycarbonyl-oxymethyl orethoxycarbonyloxymethyl, glycyloxymethyl, phenylglycyloxymethyl,(5-methyl-2-oxo-1,3-dioxolen-4-yl)-methyl and other well knownphysiologically hydrolyzable esters used, for example, in the penicillinand cephalosporin arts. Such esters may be prepared by conventionaltechniques known in the art.

Prodrug ester examples include the following groups:(1-alkanoyloxy)alkyl such as,

wherein R^(z), R^(t) and R^(y) are H, alkyl, aryl or arylalkyl; however,R^(z)O cannot be HO.

Further, examples of prodrug esters include

Other examples of suitable prodrug esters include

wherein R^(z) can be H, alkyl (such as methyl or t-butyl), arylalkyl(such as benzyl) or aryl (such as phenyl); R^(v) is H, alkyl, halogen oralkoxy, R^(u) is alkyl, aryl, arylalkyl or alkoxyl, and n₁ is 0, 1 or 2.

For further examples of prodrug derivatives (including prodrug esters),see:

a) Design of Prodrugs, edited by H. Bundgaard, (Elsevier, 1985) andMethods in Enzymology, Vol. 112, pp. 309-396, edited by K. Widder, etal. (Academic Press, 1985);

b) A Textbook of Drug Design and Development, edited by Krosgaard-Larsenand H. Bundgaard, Chapter 5, “Design and Application of Prodrugs,” by H.Bundgaard, pp. 113-191 (1991); and

c) H. Bundgaard, Advanced Drug Delivery Reviews, 8, 1-38 (1992).

The term “tautomer” refers to compounds of the formula (I) and saltsthereof that may exist in their tautomeric form, in which hydrogen atomsare transposed to other parts of the molecules and the chemical bondsbetween the atoms of the molecules are consequently rearranged. Itshould be understood that the all tautomeric forms, insofar as they mayexist, are included within the invention.

The terms pharmaceutically acceptable “salt” and “salts” refer to basicsalts formed with inorganic and organic bases. Such salts includeammonium salts; alkali metal salts, such as lithium, sodium andpotassium salts (which are preferred); alkaline earth metal salts, suchas calcium and magnesium salts; salts with organic bases, such as aminelike salts (e.g., dicyclohexylamine salt, benzathine,N-methyl-D-glucamine, and hydrabamine salts); and salts with amino acidslike arginine, lysine and the like; and zwitterions, the so-called“inner salts”. Nontoxic, pharmaceutically acceptable salts arepreferred, although other salts are also useful, e.g., in isolating orpurifying the product.

The term pharmaceutically acceptable “salt” and “salts” also includesacid addition salts. These are formed, for example, with stronginorganic acids, such as mineral acids, for example sulfuric acid,phosphoric acid or a hydrohalic acid such as HCl or HBr, with strongorganic carboxylic acids, such as alkanecarboxylic acids of 1 to 4carbon atoms which are unsubstituted or substituted, for example, byhalogen, for example acetic acid, such as saturated or unsaturateddicarboxylic acids, for example oxalic, malonic, succinic, maleic,fumaric, phthalic or terephthalic acid, such as hydroxycarboxylic acids,for example ascorbic, glycolic, lactic, malic, tartaric or citric acid,such as amino acids, (for example aspartic or glutamic acid or lysine orarginine), or benzoic acid, or with organic sulfonic acids, such as(C1-C₄) alkyl or arylsulfonic acids which are unsubstituted orsubstituted, for example by halogen, for example methanesulfonic acid orp-toluenesulfonic acid.

All stereoisomers of the compounds of the instant invention arecontemplated, either in admixture or in pure or substantially pure form.The compounds of the present invention can have asymmetric centers atany of the carbon atoms including any one or the R substituents.Consequently, compounds of formula I can exist in enantiomeric ordiastereomeric forms or in mixtures thereof. The processes forpreparation can utilize racemates, enantiomers or diastereomers asstarting materials. When diastereomeric or enantiomeric products areprepared, they can be separated by conventional methods for example,chromatographic or fractional crystallization.

The inventive compounds may be in the free or solvate (e.g. hydrate)form.

Combinations

Where desired, the compounds of structure I may be used in combinationwith one or more other types of therapeutic agents such asimmunosuppressants, anticancer agents, anti-viral agents,anti-inflammatory agents, anti-fungal agents, antibiotics, anti-vascularhyperproliferation agents, anti-depressive agents, hypolipidemic agentsor lipid-lowering agents or lipid modulating agents, antidiabeticagents, anti-obesity agents, antihypertensive agents, plateletaggregation inhibitors, and/or anti-osteoporosis agents, which may beadministered orally in the same dosage form, in a separate oral dosageform or by injection.

The immunosuppressants which may be optionally employed in combinationwith compounds of formula I of the invention include cyclosporins, forexample cyclosporin A, mycophenolate, interferon-beta, deoxyspergolin,FK-506 or Ant.-IL-2.

The anti-cancer agents which may be optionally employed in combinationwith compounds of formula I of the invention include azathiprine,5-fluorouracil, cyclophosphamide, cisplatin, methotrexate, thiotepa,carboplatin, and the like.

The anti-viral agents which may be optionally employed in combinationwith compounds of formula I of the invention include abacavir,aciclovir, ganciclovir, zidanocin, vidarabine, and the like.

The anti-inflammatory agents which may be optionally employed incombination with compounds of formula I of the invention includenon-steroidal anti-inflammatory drugs (NSAIDs) such as ibuprofen, cox-2inhibitors such as celecoxib, rofecoxib, aspirin, naproxen, ketoprofen,diclofenac sodium, indomethacin, piroxicam, steroids such as prednisone,dexamethasone, hydrocortisone, triamcinolone diacetate, gold compounds,such as gold sodium thiomalate, TNF-α inhibitors such as tenidap,anti-TNF antibodies or soluble TNF receptor, and rapamycin (sirolimus orRapamune) or derivatives thereof, infliximab (Remicade® Centocor, Inc.).CTLA-4Ig, LEA29Y, antibodies such as anti-ICAM-3, anti-IL-2 receptor(Anti-Tac), anti-CD45RB, anti-CD2, anti-CD3 (OKT-3), anti-CD4,anti-CD80, anti-CD86, monoclonal antibody OKT3, agents blocking theinteraction between CD40 and CD154 (a.k.a. “gp39”), such as antibodiesspecific for CD40 and/or CD154, fusion proteins such as etanercept,fusion proteins constructed from CD40 and/or CD154gp39 (e.g. CD40Ig andCD8gp39), inhibitors, such as nuclear translocation inhibitors, ofNF-kappa B function, such as deoxyspergualin (DSG).

The anti-fungal agents which may be optionally employed in combinationwith compounds of formula I of the invention include fluconazole,miconazole, amphotericin B, and the like.

The antibiotics which may be optionally employed in combination withcompounds of formula I of the invention include penicillin,tetracycline, amoxicillin, ampicillin, erythromycin, doxycycline,vancomycin, minocycline, clindamycin or cefalexin.

The anti-vascular hyperproliferation agents which may be optionallyemployed with compounds of formula I of the invention includemethotrexate, leflunomide, FK506 (tacrolimus, Prograf),

The hypolipidemic agent or lipid-lowering agent or lipid modulatingagents which may be optionally employed in combination with thecompounds of formula I of the invention may include 1,2,3 or more MTPinhibitors, HMG CoA reductase inhibitors, squalene synthetaseinhibitors, fibric acid derivatives, ACAT inhibitors, lipoxygenaseinhibitors, cholesterol absorption inhibitors, ileal Na⁺/bile acidcotransporter inhibitors, upregulators of LDL receptor activity, bileacid sequestrants, and/or nicotinic acid and derivatives thereof.

MTP inhibitors employed herein include MTP inhibitors disclosed in U.S.Pat. No. 5,595,872, U.S. Pat. No. 5,739,135, U.S. Pat. No. 5,712,279,U.S. Pat. No. 5,760,246, U.S. Pat. No. 5,827,875, U.S. Pat. No.5,885,983 and U.S. application Ser. No. 09/175,180 filed Oct. 20, 1998,now U.S. Pat. No. 5,962,440. Preferred are each of the preferred MTPinhibitors disclosed in each of the above patents and applications.

All of the above U.S. patents and applications are incorporated hereinby reference.

Most preferred MTP inhibitors to be employed in accordance with thepresent invention include preferred MTP inhibitors as set out in U.S.Pat. Nos. 5,739,135 and 5,712,279, and U.S. Pat. No. 5,760,246.

The most preferred MTP inhibitor is9-[4-[4-[[2-(2,2,2-trifluoroethoxy)benzoyl]amino]-1-piperidinyl]butyl]-N-(2,2,2-trifluoroethyl)-9H-fluorene-9-carboxamide

The hypolipidemic agent may be an HMG CoA reductase inhibitor whichincludes, but is not limited to, mevastatin and related compounds asdisclosed in U.S. Pat. No. 3,983,140, lovastatin (mevinolin) and relatedcompounds as disclosed in U.S. Pat. No. 4,231,938, pravastatin andrelated compounds such as disclosed in U.S. Pat. No. 4,346,227,simvastatin and related compounds as disclosed in U.S. Pat. Nos.4,448,784 and 4,450,171. Other HMG CoA reductase inhibitors which may beemployed herein include, but are not limited to, fluvastatin, disclosedin U.S. Pat. No. 5,354,772, cerivastatin disclosed in U.S. Pat. Nos.5,006,530 and 5,177,080, atorvastatin disclosed in U.S. Pat. Nos.4,681,893, 5,273,995, 5,385,929 and 5,686,104, itavastatin(Nissan/Sankyo's nisvastatin (NK-104)) disclosed in U.S. Pat. No.5,011,930, Shionogi-Astra/Zeneca visastatin (ZD-4522) disclosed in U.S.Pat. No. 5,260,440, and related statin compounds disclosed in U.S. Pat.No. 5,753,675, pyrazole analogs of mevalonolactone derivatives asdisclosed in U.S. Pat. No. 4,613,610, indene analogs of mevalonolactonederivatives as disclosed in PCT application WO 86/03488,6-[2-(substituted-pyrrol-1-yl)-alkyl)pyran-2-ones and derivativesthereof as disclosed in U.S. Pat. No. 4,647,576, Searle's SC-45355 (a3-substituted pentanedioic acid derivative) dichloroacetate, imidazoleanalogs of mevalonolactone as disclosed in PCT application WO 86/07054,3-carboxy-2-hydroxy-propane-phosphonic acid derivatives as disclosed inFrench Patent No. 2,596,393, 2,3-disubstituted pyrrole, furan andthiophene derivatives as disclosed in European Patent Application No.0221025, naphthyl analogs of mevalonolactone as disclosed in U.S. Pat.No. 4,686,237, octahydronaphthalenes such as disclosed in U.S. Pat. No.4,499,289, keto analogs of mevinolin (lovastatin) as disclosed inEuropean Patent Application No.0,142,146 A2, and quinoline and pyridinederivatives disclosed in U.S. Pat. Nos. 5,506,219 and 5,691,322.

In addition, phosphinic acid compounds useful in inhibiting HMG CoAreductase suitable for use herein are disclosed in GB 2205837.

The squalene synthetase inhibitors suitable for use herein include, butare not limited to, α-phosphono-sulfonates disclosed in U.S. Pat. No.5,712,396, those disclosed by Biller et al, J. Med. Chem., Vol. 31, No.10, pp 1869-1871 (1988), includingisoprenoid(phosphinyl-methyl)phosphonates as well as other knownsqualene synthetase inhibitors, for example, as disclosed in U.S. Pat.Nos. 4,871,721 and 4,924,024 and in Biller, S. A., Neuenschwander, K.,Ponpipom, M. M., and Poulter, C. D., Current Pharmaceutical Design, 2,1-40 (1996).

In addition, other squalene synthetase inhibitors suitable for useherein include the terpenoid pyrophosphates disclosed by P. Ortiz deMontellano et al, J. Med. Chem., 1977, 20, 243-249, the farnesyldiphosphate analog A and presqualene pyrophosphate (PSQ-PP) analogs asdisclosed by Corey and Volante, J. Am. Chem. Soc., 98, 1291-1293 (1976),phosphinylphosphonates reported by McClard, R. W. et al, J. Am. Chem.Soc., 1987, 109, 5544 (1987), and cyclopropanes reported by Capson, T.L., PhD dissertation, Dept. Med. Chem. U of Utah, Abstract, Table ofContents, pp 16, 17, 40-43, 48-51, Summary (June, 1987).

Other hypolipidemic agents suitable for use herein include, but are notlimited to, fibric acid derivatives, such as fenofibrate, gemfibrozil,clofibrate, bezafibrate, ciprofibrate, clinofibrate and the like,probucol, and related compounds as disclosed in U.S. Pat. No. 3,674,836,probucol and gemfibrozil being preferred, bile acid sequestrants such ascholestyramine, colestipol and DEAE-Sephadex (Secholex®, Policexide®)and cholestagel (Sankyo/Geltex), as well as lipostabil (Rhone-Poulenc),Eisai E-5050 (an N-substituted ethanolamine derivative), imanixil(HOE-402), tetrahydrolipstatin (THL), istigmastanylphos-phorylcholine(SPC, Roche), aminocyclodextrin (Tanabe Seiyoku), Ajinomoto AJ-814(azulene derivative), melinamide (Sumitomo), Sandoz 58-035, AmericanCyanamid CL-277,082 and CL-283,546 (disubstituted urea derivatives),nicotinic acid (niacin), acipimox, acifran, neomycin, p-aminosalicylicacid, aspirin, poly(diallylmethylamine) derivatives such as disclosed inU.S. Pat. No. 4,759,923, quaternary amine poly(diallyldimethylammoniumchloride) and ionenes such as disclosed in U.S. Pat. No. 4,027,009, andother known serum cholesterol lowering agents.

The hypolipidemic agent may be an ACAT inhibitor such as disclosed in,Drugs of the Future 24, 9-15 (1999), (Avasimibe); “The ACAT inhibitor,Cl-1011 is effective in the prevention and regression of aortic fattystreak area in hamsters”, Nicolosi et al, Atherosclerosis (Shannon,Irel). 137(1), 77-85 (1998) “The pharmacological profile of FCE 27677: anovel ACAT inhibitor with potent hypolipidemic activity mediated byselective suppression of the hepatic secretion of ApoB100-containinglipoprotein”, Ghiselli, Giancarlo, Cardiovasc. Drug Rev. (1998), 16(1),16-30; “RP 73163: a bioavailable alkylsulfinyl-diphenylimidazole ACATinhibitor”, Smith, C., et al, Bioorg. Med. Chem. Lett. 6(1), 47-50(1996); “ACAT inhibitors: physiologic mechanisms for hypolipidemic andanti-atherosclerotic activities in experimental animals”, Krause et al,Editor(s): Ruffolo, Robert R., Jr.; Hollinger, Mannfred A.,Inflammation: Mediators Pathways 173-98 (1995), Publisher: CRC, BocaRaton, Fla.; “ACAT inhibitors: potential anti-atherosclerotic agents”,Sliskovic et al, Curr. Med. Chem. 1(3), 204-25 1994); “Inhibitors ofacyl-CoA:cholesterol O-acyl transferase (ACAT) as hypocholesterolemicagents. 6. The first water-soluble ACAT inhibitor with lipid-regulatingactivity. Inhibitors of acyl-CoA:cholesterol acyl transferase (ACAT). 7.Development of a series of substitutedN-phenyl-N′-[(1-phenylcyclopentyl)methyl]ureas with enhancedhypocholesterolemic activity”, Stout et al, Chemtracts: Org. Chem. 8(6),359-62 (1995), or TS-962 (Taisho Pharmaceutical Co. Ltd).

The hypolipidemic agent may be an upregulator of LD2 receptor activitysuch as MD-700 (Taisho Pharmaceutical Co. Ltd) and LY295427 (Eli Lilly).

The hypolipidemic agent may be a cholesterol absorption inhibitorpreferably Schering-Plough's ezetimibe (SCH58235) and SCH48461 as wellas those disclosed in Atherosclerosis 115, 45-63 (1995) and J. Med.Chem. 41, 973 (1998).

The hypolipidemic agent may be an ileal Na⁺/bile acid cotransporterinhibitor such as disclosed in Drugs of the Future, 24, 425-430 (1999).

The lipid-modulating agent may be a cholesteryl ester transfer protein(CETP) inhibitor such as Pfizer's CP 529,414 (WO/0038722 and EP 818448)and Pharmacia's SC-744 and SC-795.

The ATP citrate lyase inhibitor which may be employed in the combinationof the invention may include, for example, those disclosed in U.S. Pat.No. 5,447,954.

Preferred hypolipidemic agents are pravastatin, lovastatin, simvastatin,atorvastatin, fluvastatin, cerivastatin, itavastatin and visastatin andZD-4522.

The above-mentioned U.S. patents are incorporated herein by reference.The amounts and dosages employed will be as indicated in the Physician'sDesk Reference and/or in the patents set out above.

The compounds of formula I of the invention will be employed in a weightratio to the hypolipidemic agent (were present), within the range fromabout 500:1 to about 1:500, preferably from about 100:1 to about 1:100.

The dose administered must be carefully adjusted according to age,weight and condition of the patient, as well as the route ofadministration, dosage form and regimen and the desired result.

The dosages and formulations for the hypolipidemic agent will be asdisclosed in the various patents and applications discussed above.

The dosages and formulations for the other hypolipidemic agent to beemployed, where applicable, will be as set out in the latest edition ofthe Physicians' Desk Reference.

For oral administration, a satisfactory result may be obtained employingthe MTP inhibitor in an amount within the range of from about 0.01 mg toabout 500 mg and preferably from about 0.1 mg to about 100 mg, one tofour times daily.

A preferred oral dosage form, such as tablets or capsules, will containthe MTP inhibitor in an amount of from about 1 to about 500 mg,preferably from about 2 to about 400 mg, and more preferably from about5 to about 250 mg, one to four times daily.

For oral administration, a satisfactory result may be obtained employingan HMG CoA reductase inhibitor, for example, pravastatin, lovastatin,simvastatin, atorvastatin, fluvastatin or cerivastatin in dosagesemployed as indicated in the Physician's Desk Reference, such as in anamount within the range of from about 1 to 2000 mg, and preferably fromabout 4 to about 200 mg.

The squalene synthetase inhibitor may be employed in dosages in anamount within the range of from about 10 mg to about 2000 mg andpreferably from about 25 mg to about 200 mg.

A preferred oral dosage form, such as tablets or capsules, will containthe HMG CoA reductase inhibitor in an amount from about 0.1 to about 100mg, preferably from about 0.5 to about 80 mg, and more preferably fromabout 1 to about 40 mg.

A preferred oral dosage form, such as tablets or capsules will containthe squalene synthetase inhibitor in an amount of from about 10 to about500 mg, preferably from about 25 to about 200 mg.

The hypolipidemic agent may also be a lipoxygenase inhibitor including a15-lipoxygenase (15-LO) inhibitor such as benzimidazole derivatives asdisclosed in WO 97/12615, 15-LO inhibitors as disclosed in WO 97/12613,isothiazolones as disclosed in WO 96/38144, and 15-LO inhibitors asdisclosed by Sendobry et al “Attenuation of diet-induced atherosclerosisin rabbits with a highly selective 15-lipoxygenase inhibitor lackingsignificant antioxidant properties”, Brit. J. Pharmacology 120,1199-1206 (1997), and Cornicelli et al, “15-Lipoxygenase and itsInhibition: A Novel Therapeutic Target for Vascular Disease”, CurrentPharmaceutical Design, 5, 11-20 (1999).

The compounds of formula I and the hypolipidemic agent may be employedtogether in the same oral dosage form or in separate oral dosage formstaken at the same time.

The compositions described above may be administered in the dosage formsas described above in single or divided doses of one to four timesdaily. It may be advisable to start a patient on a low dose combinationand work up gradually to a high dose combination.

The preferred hypolipidemic agent is pravastatin, simvastatin,lovastatin, atorvastatin, fluvastatin or cerivastatin as well as niacinand/or cholestagel.

The other antidiabetic agent which may be optionally employed incombination with the compound of formula I may be 1,2,3 or moreantidiabetic agents or antihyperglycemic agents including insulinsecretagogues or insulin sensitizers, or other antidiabetic agentspreferably having a mechanism of action different from the compounds offormula I of the invention, which may include biguanides, sulfonylureas, glucosidase inhibitors, PPAR γ agonists, such asthiazolidinediones, aP2 inhibitors, dipeptidyl peptidase IV (DP4)inhibitors, SGLT2 inhibitors, and/or meglitinides, as well as insulin,and/or glucagon-like peptide-1 (GLP-1).

The other antidiabetic agent may be an oral antihyperglycemic agentpreferably a biguanide such as metformin or phenformin or salts thereof,preferably metformin HCl.

Where the antidiabetic agent is a biguanide, the compounds of structureI will be employed in a weight ratio to biguanide within the range fromabout 0.001:1 to about 10:1, preferably from about 0.01:1 to about 5:1.

The other antidiabetic agent may also preferably be a sulfonyl urea suchas glyburide (also known as glibenclamide), glimepiride (disclosed inU.S. Pat. No. 4,379,785), glipizide, gliclazide or chlorpropamide, otherknown sulfonylureas or other antihyperglycemic agents which act on theATP-dependent channel of the □-cells, with glyburide and glipizide beingpreferred, which may be administered in the same or in separate oraldosage forms.

The compounds of structure I will be employed in a weight ratio to thesulfonyl urea in the range from about 0.01:1 to about 100:1, preferablyfrom about 0.02:1 to about 5:1.

The oral antidiabetic agent may also be a glucosidase inhibitor such asacarbose (disclosed in U.S. Pat. No. 4,904,769) or miglitol (disclosedin U.S. Pat. No. 4,639,436), which may be administered in the same or ina separate oral dosage forms.

The compounds of structure I will be employed in a weight ratio to theglucosidase inhibitor within the range from about 0.01:1 to about 100:1,preferably from about 0.05:1 to about 10:1.

The compounds of structure I may be employed in combination with a PPARγ agonist such as a thiazolidinedione oral anti-diabetic agent or otherinsulin sensitizers (which has an insulin sensitivity effect in NIDDMpatients) such as troglitazone (Warner-Lambert's Rezulin®, disclosed inU.S. Pat. No. 4,572,912), rosiglitazone (SKB), pioglitazone (Takeda),Mitsubishi's MCC-555 (disclosed in U.S. Pat. No. 5,594,016),Glaxo-Welcome's GL-262570, englitazone (CP-68722, Pfizer) ordarglitazone (CP-86325, Pfizer, isaglitazone (MIT/J&J), JTT-501(JPNT/P&U), L-895645 (Merck), R-119702 (Sankyo/WL), NN-2344 (Dr.Reddy/NN), or YM-440 (Yamanouchi), preferably rosiglitazone andpioglitazone.

The compounds of structure I will be employed in a weight ratio to thethiazolidinedione in an amount within the range from about 0.01:1 toabout 100:1, preferably from about 0.05 to about 10:1.

The sulfonyl urea and thiazolidinedione in amounts of less than about150 mg oral antidiabetic agent may be incorporated in a single tabletwith the compounds of structure I.

The compounds of structure I may also be employed in combination with aantihyperglycemic agent such as insulin or with glucagon-like peptide-1(GLP-1) such as GLP-1(1-36) amide, GLP-1(7-36) amide, GLP-1(7-37) (asdisclosed in U.S. Pat. No. 5,614,492 to Habener, the disclosure of whichis incorporated herein by reference), as well as AC2993 (Amylin) andLY-315902 (Lilly), which may be administered via injection, intranasal,inhalation or by transdermal or buccal devices.

Where present, metformin, the sulfonyl ureas, such as glyburide,glimepiride, glipyride, glipizide, chlorpropamide and gliclazide and theglucosidase inhibitors acarbose or miglitol or insulin (injectable,pulmonary, buccal, or oral) may be employed in formulations as describedabove and in amounts and dosing as indicated in the Physician's DeskReference (PDR).

Where present, metformin or salt thereof may be employed in amountswithin the range from about 500 to about 2000 mg per day which may beadministered in single or divided doses one to four times daily.

Where present, the thiazolidinedione anti-diabetic agent may be employedin amounts within the range from about 0.01 to about 2000 mg/day whichmay be administered in single or divided doses one to four times perday.

Where present insulin may be employed in formulations, amounts anddosing as indicated by the Physician's Desk Reference.

Where present GLP-1 peptides may be administered in oral buccalformulations, by nasal administration or parenterally as described inU.S. Pat. No. 5,346,701 (TheraTech), U.S. Pat. Nos. 5,614,492 and5,631,224 which are incorporated herein by reference.

The other antidiabetic agent may also be a PPAR α/γ dual agonist such asAR-HO39242 (Astra/Zeneca), GW-409544 (Glaxo-Wellcome), KRP297 (KyorinMerck) as well as those disclosed by Murakami et al, “A Novel InsulinSensitizer Acts As a Coligand for Peroxisome Proliferation-ActivatedReceptor Alpha (PPAR alpha) and PPAR gamma. Effect on PPAR alphaActivation on Abnormal Lipid Metabolism in Liver of Zucker Fatty Rats”,Diabetes 47, 1841-1847 (1998).

The antidiabetic agent may be an SGLT2 inhibitor such as disclosed inU.S. application Ser. No. 09/679,027, filed Oct. 4, 2000 employingdosages as set out therein. Preferred are the compounds designated aspreferred in the above application.

The antidiabetic agent may be an aP2 inhibitor such as disclosed in U.S.application Ser. No. 09/391,053, filed Sep. 7, 1999, and in U.S.application Ser. No. 09/519,079, filed Mar. 6, 2000 employing dosages asset out herein. Preferred are the compounds designated as preferred inthe above application.

The antidiabetic agent may be a DP4 inhibitor such as disclosed in U.S.application Ser. No. 09/788,173 filed Feb. 16, 2001 , WO99/38501,WO99/46272, WO99/67279 (PROBIODRUG), WO99/67278 (PROBIODRUG), WO99/61431(PROBIODRUG), NVP-DPP728A(1-[[[2-[(5-cyanopyridin-2-yl)amino]ethyl]amino]acetyl]-2-cyano-(S)-pyrrolidine)(Novartis) (preferred) as disclosed by Hughes et al, Biochemistry,38(36), 11597-11603, (1999), TSL-225(tryptophyl-1,2,3,4-tetrahydro-isoquinoline-3-carboxylic acid (disclosedby Yamada et al, Bioorg. & Med. Chem. Lett. 8 1537-1540 (1998),2-cyanopyrrolidides and 4-cyanopyrrolidides as disclosed by Ashworth etal, Bioorg. & Med. Chem. Lett., Vol. 6, No. 22, pp 1163-1166 and2745-2748 (1996) employing dosages as set out in the above references.

The meglitinide which may optionally be employed in combination with thecompound of formula I of the invention may be repaglinide, nateglinide(Novartis) or KAD1229 (PF/Kissei), with repaglinide being preferred.

The compound of formula I will be employed in a weight ratio to themeglitinide, PPAR γ agonist, PPAR α/γ dual agonist, aP2 inhibitor, DP4inhibitor or SGLT2 inhibitor within the range from about 0.01:1 to about100:1, preferably from about 0.05 to about 10:1.

The other type of therapeutic agent which may be optionally employedwith a compound of formula I may be 1, 2, 3 or more of an anti-obesityagent including a beta 3 adrenergic agonist, a lipase inhibitor, aserotonin (and dopamine) reuptake inhibitor, an aP2 inhibitor, a thyroidreceptor agonist and/or an anorectic agent.

The beta 3 adrenergic agonist which may be optionally employed incombination with a compound of formula I may be AJ9677(Takeda/Dainippon), L750355 (Merck), or CP331648 (Pfizer) or other knownbeta 3 agonists as disclosed in U.S. Pat. Nos. 5,541,204, 5,770,615,5,491,134, 5,776,983 and 5,488,064, with AJ9677, L750,355 and CP331648being preferred.

The lipase inhibitor which may be optionally employed in combinationwith a compound of formula I may be orlistat or ATL-962 (Alizyme), withorlistat being preferred.

The serotonin (and dopoamine) reuptake inhibitor which may be optionallyemployed in combination with a compound of formula I may be sibutramine,topiramate (Johnson & Johnson) or axokine (Regeneron), with sibutramineand topiramate being preferred.

The thyroid receptor agonist which may be optionally employed incombination with a compound of formula I may be a thyroid receptorligand as disclosed in WO97/21993 (U. Cal SF), WO99/00353 (KaroBio),(KaroBio), WO2000039077 (KaroBio, particularly in priority documentGB98/28442), and U.S. Provisional Application 60/183,223 filed Feb. 17,2000, with compounds of the KaroBio applications and the above U.S.provisional application being preferred.

The anorectic agent which may be optionally employed in combination witha compound of formula I may be dexamphetamine, phentermine,phenylpropanolamine or mazindol, with dexamphetamine being preferred.

The various anti-obesity agents described above may be employed in thesame dosage form with the compound of formula I or in different dosageforms, in dosages and regimens as generally known in the art or in thePDR.

The antihypertensive agents which may be employed in combination withthe compound of formula I of the invention include ACE inhibitors,angiotensin II receptor antagonists, NEP/ACE inhibitors, as well ascalcium channel blockers, β-adrenergic blockers and other types ofantihypertensive agents including diuretics.

The angiotensin converting enzyme inhibitor which may be employed hereinincludes those containing a mercapto (—S—) moiety such as substitutedproline derivatives, such as any of those disclosed in U.S. Pat. No.4,046,889 to Ondetti et al mentioned above, with captopril, that is,1-[(2S)-3-mercapto-2-methylpropionyl]-L-proline, being preferred, andmercaptoacyl derivatives of substituted prolines such as any of thosedisclosed in U.S. Pat. No. 4,316,906 with zofenopril being preferred.

Other examples of mercapto containing ACE inhibitors that may beemployed herein include rentiapril (fentiapril, Santen) disclosed inClin. Exp. Pharmacol. Physiol. 10:131 (1983); as well as pivopril andYS980.

Other examples of angiotensin converting enzyme inhibitors which may beemployed herein include any of those disclosed in U.S. Pat. No.4,374,829 mentioned above, withN-(1-ethoxycarbonyl-3-phenylpropyl)-L-alanyl-L-proline, that is,enalapril, being preferred, any of the phosphonate substituted amino orimino acids or salts disclosed in U.S. Pat. No. 4,452,790 with(S)-1-[6-amino-2-[[hydroxy-(4-phenylbutyl)phosphinyl]oxy]-1-oxohexyl]-L-prolineor (ceronapril) being preferred, phosphinylalkanoyl prolines disclosedin U.S. Pat. No. 4,168,267 mentioned above with fosinopril beingpreferred, any of the phosphinylalkanoyl substituted prolines disclosedin U.S. Pat. No. 4,337,201, and the phosphonamidates disclosed in U.S.Pat. No. 4,432,971 discussed above.

Other examples of ACE inhibitors that may be employed herein includeBeecham's BRL 36,378 as disclosed in European Patent Application Nos.80822 and 60668; Chugai's MC-838 disclosed in C.A. 102:72588v and Jap.J. Pharmacol. 40:373 (1986); Ciba-Geigy's CGS 14824(3-([1-ethoxycarbonyl-3-phenyl-(1S)-propyl]amino)-2,3,4,5-tetrahydro-2-oxo-1-(3S)-benzazepine-1acetic acid HCl) disclosed in U.K. Patent No. 2103614 and CGS 16,617(3(S)-[[(1S)-5-amino-1-carboxypentyl]amino]-2,3,4,5-tetrahydro-2-oxo-1H-1-benzazepine-1-ethanoicacid) disclosed in U.S. Pat. No. 4,473,575; cetapril (alacepril,Dainippon) disclosed in Eur. Therap. Res. 39:671 (1986); 40:543 (1986);ramipril (Hoechsst) disclosed in Euro. Patent No. 79-022 and Curr. Ther.Res. 40:74 (1986); Ru 44570 (Hoechst) disclosed in Arzneimittelforschung34:1254 (1985), cilazapril (Hoffman-LaRoche) disclosed in J. Cardiovasc.Pharmacol. 9:39 (1987); R 31-2201 (Hoffman-LaRoche) disclosed in FEBSLett. 165:201 (1984); lisinopril (Merck), indalapril (delapril)disclosed in U.S. Pat. No. 4,385,051; indolapril (Schering) disclosed inJ. Cardiovasc. Pharmacol. 5:643, 655 (1983), spirapril (Schering)disclosed in Acta. Pharmacol. Toxicol. 59 (Supp. 5):173 (1986);perindopril (Servier) disclosed in Eur. J. clin. Pharmacol. 31:519(1987); quinapril (Warner-Lambert) disclosed in U.S. Pat. No. 4,344,949and CI925 (Warner-Lambert)([3S-[2[R(*)R(*)]]3R(*)]-2-[2-[[1-(ethoxy-carbonyl)-3-phenylpropyl]amino]-1-oxopropyl]-1,2,3,4-tetrahydro-6,7-dimethoxy-3-isoquinolinecarboxylicacid HCl) disclosed in Pharmacologist 26:243, 266 (1984), WY-44221(Wyeth) disclosed in J. Med. Chem. 26:394 (1983).

Preferred ACE inhibitors are captopril, fosinopril, enalapril,lisinopril, quinapril, benazepril, fentiapril, ramipril and moexipril.

NEP/ACE inhibitors may also be employed herein in that they possessneutral endopeptidase (NEP) inhibitory activity and angiotensinconverting enzyme (ACE) inhibitory activity. Examples of NEP/ACEinhibitors suitable for use herein include those disclosed in U.S. Pat.Nos. 5,362,727, 5,366,973, 5,225,401, 4,722,810, 5,223,516, 4,749,688,U.S. Pat. No. 5,552,397, U.S. Pat. No. 5,504,080, U.S. Pat. No.5,612,359,U.S. Pat. No. 5,525,723, European Patent Application 0599,444,0481,522, 0599,444, 0595,610, European Patent Application 0534363A2,534,396 and 534,492, and European Patent Application 0629627A2.

Preferred are those NEP/ACE inhibitors and dosages thereof which aredesignated as preferred in the above patents/applications which U.S.patents are incorporated herein by reference; most preferred areomapatrilat, BMS 189,921([S—(R*,R*)]-hexahydro-6-[(2-mercapto-1-oxo-3-phenylpropyl)amino]-2,2-dimethyl-7-oxo-1H-azepine-1-aceticacid (gemopatrilat)) and CGS 30440.

The angiotensin II receptor antagonist (also referred to herein asangiotensin II antagonist or AII antagonist) suitable for use hereinincludes, but is not limited to, irbesartan, losartan, valsartan,candesartan, telmisartan, tasosartan or eprosartan, with irbesartan,losartan or valsartan being preferred.

A preferred oral dosage form, such as tablets or capsules, will containthe ACE inhibitor or AII antagonist in an amount within the range fromabut 0.1 to about 500 mg, preferably from about 5 to about 200 mg andmore preferably from about 10 to about 150 mg.

For parenteral administration, the ACE inhibitor, angiotensin IIantagonist or NEP/ACE inhibitor will be employed in an amount within therange from about 0.005 mg/kg to about 10 mg/kg and preferably from about0.01 mg/kg to about 1 mg/kg.

Where a drug is to be administered intravenously, it will be formulatedin conventional vehicles, such as distilled water, saline, Ringer'ssolution or other conventional carriers.

It will be appreciated that preferred dosages of ACE inhibitor and AIIantagonist as well as other antihypertensives disclosed herein will beas set out in the latest edition of the Physician's Desk Reference(PDR).

Other examples of preferred antihypertensive agents suitable for useherein include omapatrilat (Vanlev®) amlodipine besylate (Norvasc®),prazosin HCl (Minipress®), verapamil, nifedipine, nadolol, diltiazem,felodipine, nisoldipine, isradipine, nicardipine, atenolol, carvedilol,sotalol, terazosin, doxazosin, propranolol, and clonidine HCl(Catapres®).

Diuretics which may be employed in combination with compounds of formulaI include hydrochlorothiazide, torasemide, furosemide, spironolactono,and indapamide.

Antiplatelet agents which may be employed in combination with compoundsof formula I of the invention include aspirin, clopidogrel, ticlopidine,dipyridamole, abciximab, tirofiban, eptifibatide, anagrelide, andifetroban, with clopidogrel and aspirin being preferred.

The antiplatelet drugs may be employed in amounts as indicated in thePDR. Ifetroban may be employed in amounts as set out in U.S. Pat. No.5,100,889.

Antiosteoporosis agents suitable for use herein in combination with thecompounds of formula I of the invention include parathyroid hormone orbisphosphonates, such as MK-217 (alendronate) (Fosamax®).

Dosages employed for the above drugs will be as set out in thePhysician's Desk Reference.

Pharmaceutical Formulations

The pharmaceutical composition of the invention includes apharmaceutically acceptable carrier, adjuvant or vehicle that may beadministered to a subject, together with a compound of the presentinvention, and which does not destroy the pharmacological activitythereof. Pharmaceutically acceptable carriers, adjuvants and vehiclesthat may be used in the pharmaceutical compositions of the presentinvention include, but are not limited to, the following: ionexchangers, alumina, aluminum stearate, lecithin, self-emulsifying drugdelivery systems (“SEDDS”) such as d(-tocopherol polyethyleneglycol 1000succinate), surfactants used in pharmaceutical dosage forms such asTweens or other similar polymeric delivery matrices, serum proteins suchas human serum albumin, buffer substances such as phosphates, glycine,sorbic acid, potassium sorbate, partial glyceride mixtures of saturatedvegetable fatty acids, water, salts or electrolytes such as protaminesulfate, disodium hydrogen phosphate, potassium hydrogen phosphate,sodium chloride, zinc salts, colloidal silica, magnesium trisilicate,polyvinyl pyrrolidone, cellulose-based substances, polyethylene glycol,sodium carboxymethylcellulose, polyacrylates, waxes,polyethylene-polyoxypropylene-block polymers, polyethylene glycol andwool fat. Cyclodextrins such as α-, β- and γ-cyclodextrin, or chemicallymodified derivatives such as hydroxyalkylcyclodextrins, including 2- and3-hydroxypropyl-β-cyclodextrins, or other solubilized derivatives mayalso be used to enhance delivery of the modulators of the presentinvention.

The compositions of the present invention may contain other therapeuticagents as described below, and may be formulated, for example, byemploying conventional solid or liquid vehicles or diluents, as well aspharmaceutical additives of a type appropriate to the mode of desiredadministration (for example, excipients, binders, preservatives,stabilizers, flavors, etc.) according to techniques such as those wellknown in the art of pharmaceutical formulation.

The compounds of the invention may be administered by any suitablemeans, for example, orally, such as in the form of tablets, capsules,granules or powders; sublingually; buccally; parenterally, such as bysubcutaneous, intravenous, intramuscular, or intrasternal injection orinfusion techniques (e.g., as sterile injectable aqueous or non-aqueoussolutions or suspensions); nasally such as by inhalation spray;topically, such as in the form of a cream or ointment; or rectally suchas in the form of suppositories; in dosage unit formulations containingnon-toxic, pharmaceutically acceptable vehicles or diluents. Thecompounds of the invention may, for example, be administered in a formsuitable for immediate release or extended release. Immediate release orextended release may be achieved by the use of suitable pharmaceuticalcompositions including the compounds of the invention, or, particularlyin the case of extended release, by the use of devices such assubcutaneous implants or osmotic pumps. The compounds of the inventionmay also be administered liposomally.

Exemplary compositions for oral administration include suspensions whichmay contain, for example, microcrystalline cellulose for imparting bulk,alginic acid or sodium alginate as a suspending agent, methylcelluloseas a viscosity enhancer, and sweeteners or flavoring agents such asthose known in the art; and immediate release tablets which may contain,for example, microcrystalline cellulose, dicalcium phosphate, starch,magnesium stearate and/or lactose and/or other excipients, binders,extenders, disintegrants, diluents and lubricants such as those known inthe art. The present compunds may also be delivered through the oralcavity by sublingual and/or buccal administration. Molded tablets,compressed tablets or freeze-dried tablets are exemplary forms which maybe used. Exemplary compositions include those formulating thecompound(s) of the invention with fast dissolving diluents such asmannitol, lactose, sucrose and/or cyclodextrins. Also included in suchformulations may be high molecular weight excipients such as celluloses(Avicel) or polyethylene glycols (PEG). Such formulations may alsoinclude an excipient to aid mucosal adhesion such as hydroxy propylcellulose (HPC), hydroxy propyl methyl cellulose (HPMC), sodium carboxymethyl cellulose (SCMC), maleic anhydride copolymer (e.g., Gantrez), andagents to control release such as polyacrylic copolymer (e.g., Carbopol934). Lubricants, glidants, flavors, coloring agents and stabilizers mayalso be added for ease of fabrication and use.

Exemplary compositions for nasal aerosol or inhalation administrationinclude solutions in saline which may contain, for example, benzylalcohol or other suitable preservatives, absorption promoters to enhancebioavailability, and/or other solubilizing or dispersing agents such asthose known in the art.

Exemplary compositions for parenteral administration include injectablesolutions or suspensions which may contain, for example, suitablenon-toxic, parenterally acceptable diluents or solvents, such asmannitol, 1,3-butanediol, water, Ringer's solution, an isotonic sodiumchloride solution, or other suitable dispersing or wetting andsuspending agents, including synthetic mono- or diglycerides, and fattyacids, including oleic acid. The term “parenteral” as used hereinincludes subcutaneous, intracutaneous, intravenous, intramuscular,intraarticular, intraarterial, intrasynovial, intrasternal, intrathecal,intralesional and intracranial injection or infusion techniques.

Exemplary compositions for rectal administration include suppositorieswhich may contain, for example, a suitable non-irritating excipient,such as cocoa butter, synthetic glyceride esters or polyethyleneglycols, which are solid at ordinary temperatures, but liquify and/ordissolve in the rectal cavity to release the drug.

Exemplary compositions for topical administration include a topicalcarrier such as Plastibase (mineral oil gelled with polyethylene).

The effective amount of a compound of the present invention may bedetermined by one of ordinary skill in the art, and includes exemplarydosage amounts for an adult human of from about 0.1 to 500 mg/kg of bodyweight of active compound per day, or between 5 and 2000 mg per daywhich may be administered in a single dose or in the form of individualdivided doses, such as from 1 to 5 times per day. It will be understoodthat the specific dose level and frequency of dosage for any particularsubject may be varied and will depend upon a variety of factorsincluding the activity of the specific compound employed, the metabolicstability and length of action of that compound, the species, age, bodyweight, general health, sex and diet of the subject, the mode and timeof administration, rate of excretion, drug combination, and severity ofthe particular condition. Preferred subjects for treatment includeanimals, most preferably mammalian species such as humans, and domesticanimals such as dogs, cats and the like.

A typical capsule for oral administration contains compounds ofstructure I (250 mg), lactose (75 mg) and magnesium stearate (15 mg).The mixture is passed through a 60 mesh sieve and packed into a No. 1gelatin capsule.

A typical injectable preparation is produced by aseptically placing 250mg of compounds of structure I into a vial, aseptically freeze-dryingand sealing. For use, the contents of the vial are mixed with 2 mL ofphysiological saline, to produce an injectable preparation.

The compounds of formula (I) of the invention are glucocorticoidreceptor modulators as shown either by their ability to bindglucocorticoid receptors in GR binding assays, or by their ability toinhibit AP-1 activity as indicated in cellular transrespressionalassays, and cause none to minimal transactivation as indicated incellular transscriptional assays.

Compounds of the invention, including the compounds described in theexamples hereof, have been tested in at least one of the assaysdescribed below and have glucocorticoid receptor (GR)/Dexamethasone(Dex) inhibition activity (>25% at 10 μM, preferably >95% at 10 μM)and/or AP-1 inhibition activity (EC₅₀ less than 15 μM).

Identical and/or similar assays are described in copending U.S. patentapplication Ser. No. 10/621,807, filed Jul. 18, 2002 which isincorporated in its entireity herein by reference.

GR (Dex) Binding Assay

In order to measure the binding of compounds to Site I on theglucocorticoid receptor a commercially available kit was used(Glucocorticoid receptor competitor assay kit, Panvera Co., Madison,Wis.). Briefly, a cell lysate containing recombinantly expressed humanfull-length glucocorticoid receptor was mixed with a fluorescentlylabeled glucocorticoid (4 nM FITC-dexamethasone) plus or minus testmolecule. After one hour at room temperature, the fluorescencepolarization (FP) of the samples were measured. The FP of a mixture ofreceptor, fluorescent probe (i.e. FITC-dexamethasone) and 1 mMdexamethasone represented background fluorescence or 100% inhibition,whereas, the FP of the mixture without dexamethasone was taken to be100% binding. The percentage inhibition of test molecules were thencompared to the sample with 1 mM dexamethasone and expressed as %relative binding activity with dexamethasone being 100% and noinhibition is 0%. Test molecules were analyzed in the concentrationrange from 0.1 nM to 40 μM.

Site I binding assays for any NHR (Nuclear Hormone Receptor) areconducted similarly to the above. An appropriate cell lysate or purifiedNHR is used as the source of the NHR. The fluorescent probe andunlabeled competitor are appropriate for the specific NHR, i.e. areligands for the specific NHR.

Cellular Transrepressional Assay

To measure the ability of test molecules to inhibit AP-1 inducedtranscriptional activity we utilized an A549 cell which was stablytransfected with a plasmid containing 7× AP-1 DNA binding sites(pAP-1-Luc plasmid, Stratagene Co. La Jolla, Calif.) followed by thegene for luciferase. Cells were activated with 10 ng/ml of phorbolmyristic acid (PMA) plus or minus test molecules for 7 hours. After 7hours a luciferase reagent was added to measure luciferase enzymaticactivity in the cell. After a 10 minute incubation of luciferase reagentwith cells, luminescence was measured in a TopCount luminescencecounter. Repression of AP-1 activity was calculated as the percentagedecrease in the signal induced by PMA alone. Test molecules wereanalyzed in the concentration range from 0.1 nM to 40 μM. EC50s weredetermined by using standard curve fitting methods such as Excel fit(Microsoft Co.). An EC50 is the test molecule concentration at whichthere is a 50% repression of the maximal inhibition of transcription,i.e. a 50% reduction of AP-1 activity.

Other reporters and cell lines also may be used in a cellulartransrepressional assay. A similar assay is performed in which NF-κBactivity is measured. A plasmid containing NF-κB DNA binding sites isused, such as pNF-kB-Luc, (Stratagene, LaJolla Calif.), and PMA oranother stimulus, such as TNF-α or lipopolysaccharide, is used toactivate the NF-κB pathway. NF-κB assays similar to that described inYamamoto K., et al., J Biol Chem December 29;270(52):31315-20 (1995) maybe used.

The cellular transrepressional assays described above may be used tomeasure transrepression by any NHR. One of skill in the art willunderstand that assays may require the addition of components, such as astimulus (eg. PMA, lipopolysaccharide, TNF-α, etc) which will inducetranscription mediated by AP-1 or NF-κB. Additionally, AR mediatedtransrepression may be measured by the assay described in Palvimo J J,et al. J Biol Chem September 27;271(39):24151-6 (1996), and PR mediatedtransrepression may be measured by the assay described in Kalkhoven E.,et al. J Biol Chem March 15;271(11):6217-24 (1996).

Preparations

The preparations set out below are for the synthesis of reagents thatwere not obtained from commercial sources and were employed for thepreparation of compounds of formula I of the invention. All chemicalstructures in the tables and schemes are racemic unless specifiedotherwise.

Reverse-phase preparative high performance liquid chromatography(“HPLC”) was performed with Shimadzu SA liquid chromatographs using YMCS5 ODS columns (20×100, 20×250, or 30×250 millimeter (“mm”)). Gradientelution was performed with methanol (“MeOH”)/water mixtures in thepresence of 0.1% trifluoroacetic acid (“TFA”).

Analytical HPLC Method Employed in Characterization of Examples

Analytical HPLC was performed on Shimadzu LC10AS liquid chromatographsusing the following method:

Linear gradient of 0 to 100% solvent B over 4 minutes (“min”), with 1minute (“min”) hold at 100% B.

Ultraviolet (“UV”) visualization at 220 nanometers (“nm”)

Column: YMC S5 ODS Ballistic 4.6×50 mm

Flow rate: 4 milliliters (“mL”)/min

Solvent A: 0.2% phosphoric acid, 90% water, 10% methanol Solvent B: 0.2%phosphoric acid, 90% methanol, 10% water

Preparation 1

To a solution of anthracene-1-carboxylic acid (2.5 g, 11.26 mmol) in THF(30 ml) was added DMF (1.75 ml, 22.52 mmol). The solution was cooled to0° C. and oxalyl dichloride (2M in CH₂Cl₂, 22.5 ml, 45 mmol) was addeddropwise. The reaction solution was stirred at room temperature for 2hours and then was cannulated into a solution of concentrated ammoniumhydroxide (25 ml) in a 3-necked flask cooled at 0° C. The reactionmixture was allowed to warm to room temperature and stirred for 24hours. The white precipitate was filtered and washed with water to giveanthracene-1-carboxylic acid amide as an off-white solid (2.58 g, 100%yield). LC/MS (m/z 222.15 (M+H)⁺); HPLC (Column: Shimadzu VP-0DS, C-18Ballistic; 10-90% aq CH30H/0.1% H3PO4, same for compounds hereafterunless noted) Rt: 2.872 min.

Step 2

A 75 ml sealed tube was charged with anthracene-1-carboxylic acid amide(2.345 g, 10.26 mmol), hydroquinone (0.113 g, 1.03 mmol), methacrylicacid (2.6 ml, 30.78 mmol) in a solution of toluene (30 ml) andnitrobenzene (3 ml). The reaction was heated at 155° C. for 24 hours.The reaction was cooled, filtered and purified by the preparative HPLC(column: YMC, C-18 Ballistic, 30×100 mm; 10-90% aq CH3OH/0.1% TFA, 25mL/min. flow rate, 220 nm detection wavelength, same for compoundshereafter unless noted) to yield the 4 regio-isomers 1a, 1b, 1c and 1d.The regio-chemistry for 1b, 1c, and 1d were proved by x-ray analysis.

Isomer 1a, white solid, (403 4 mg, 12.8% yield). LC/MS (m/z 306.3(M−H)⁺); HPLC Rt: 2.354 min.

Isomer 1b, white solid (285 mg, 9.1% yield). LC/MS (n/z 306.3 (M−H)⁺);HPLC Rt: 2.527 min.

Isomer 1c, white solid (610 mg, 19.4% yield). LC/MS (m/z 306.3 (M−H)⁺);HPLC Rt: 2.813 min.

Isomer 1d, white solid (310.7 mg, 10%). LC/MS (m/z 306.3 (M−H)⁺); HPLCRt: 2.920 min.

Preparation 2

The product of Preparation 1, 1c (180 mg) was resolved into itscorresponding enantiomers, 1c-(R) and 1c-(S) by chiral preparative HPLCwith the following conditions, Column: Chiralpak®-AD, 2×50 cm, Mobilephase: CO2/methanol/trifluoroacetic acid: 80/20/0.1 (vol/vol/vol),Temperature: ambient, Flowrate: 60 mL/min, Detection: UV (220 nm).Retention times for the fast eluting enantiomer 2a (81 mg), 5.59 min,slow eluting enantiomer 2b (81 mg), 7.70 min. Analytical HPLCconditions, Column: Chiralpak®-AD, 4.6×250 mm, Mobile phase:CO2/methanol/trifluoroacetic acid: 80/20/0.1 (vol/vol/vol), Temperature:ambient, Flowrate: 1.5 mL/min, Detection: UV (250 nm). Retention times:2a, 4.50 min; 2b, 6.11 min.

EXAMPLES

The following Examples illustrate embodiments of the inventive compoundsand starting materials, and are not intended to limit the scope of theclaims.

Example 1

To a solution of the acid of Preparation 1c (23 mg, 0.075 mmol) in CH3CN(1.5 mL) were added 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimidehydrochloride (EDC) (26.2 mg, 0.136 mmol) and 1-hydroxy-7-benzotriazole(HOBt) (18.5 mg, 0.136 mmol). After stirring for 5 minutes, to thesolution were added 4-(4-methyl-naphthalen-1-yl)-thiazol-2-ylamine (44mg, 0.18 mmol) and diisopropylethyl amine (59 mg, 0.084 ml, 0.22 mmol).The reaction was heated at 90° C. for 18 hours. The reaction wasfiltered, concentrated and purified by preparative HPLC to give thetitle compound of Example 1 (13.3 mg, 34% yield). LC/MS (m/z 530.19(M+H)⁺); HPLC Rt: 4.00 min.

Examples 2 to 14

In a similar manner to Example 1, Examples 2-14 were prepared via thecoupling reactions of acids of Preparation 1a to 1d and the appropriateamines. (Compounds are racemic unless noted) Example HPLC MS No.Structure Rt: minute [m/z (M+H)] 2

4.02 530.23 3

4.08 530.36 4

4.12 530.25 5

3.67 480.18 6

2.50 463.25 7

2.97 517.18 8

3.61 510.18 9

3.81 510.06 10

3.72 510.13 11

4.05 534.15 12

3.39 462.21 13

3.62 510.19 14

2.89 557.24

Examples 15 to 20

In a similar manner to Example 1, Examples 15-20 were prepared via thecoupling reactions of the chiral acids of Preparation 2a and 2b with theappropriate amines respectively. Example HPLC MS No. Structure Rt:minute [m/z (M+H)] 15

2.71 557.22 16

2.71 557.22 17

3.39 462.15 18

3.40 462.14 19

3.68 510.23 20

3.69 510.24

Example 21

To a solution of the title compound of Example 11 (30 mg, 0.0567 mmol)in 1.5 ml DMF was added cyanuric chloride (20.7 ml, 0.113 mmol) at 0° C.The reaction was stirred at room temperature for 6 hours. Diluted with10% methanol in water the crude product was purified by prep HPLC togive the title compound of Example 21 as a white solid (24.5 mg, 84%yield). LC/MS (m/z 516.16 (M+H)⁺); HPLC Rt: 4.33 min.

Example 22

To a solution of the title compound of Example 21 (19.5 mg, 0.038 mmol)in 1.5 ml THF was added Lithium aluminum hydride (LiAlH₄, 1M in THF,0.075 ml, 0.075 mmol) at 0° C. The reaction was stirred at roomtemperature overnight. Additional 0.2 ml LiAlH₄ THF solution was added.The reaction was stired at room temperature for 2 hours. The reactionwas quenched with water, filtered and purified by prep HPLC to give thetitle compound (TFA salt) of Example 22 as a white solid (5 mg, 25%yield). LC/MS (m/z 520.18 (M+H)⁺); HPLC Rt: 3.48 min

Example 23

Example 23

Step 1 (Reference: Tet. Lett. 1977, 38, 2367)

To a solution of the compound of Preparation 1a (31 mg, 0.1 mmol) in 2ml methanol was added N,N-dimethlformamide dimethyl acetal (DMF-DMA,0.040 ml, 0.3 mmol). The reaction was stirred at 60° C. for 6 hours andat 80° C. overnight. To the reaction mixture was added sodium methoxide(10.8 mg, 0.2 mmol) and heated at 80° C. for 2 hours. The crude productwas filtered, and purified by prep HPLC to give the ester acid (19 mg,59% yield). LC/MS (m/z 359.24 (M+H)⁺); HPLC Rt: 3.792 min

Step 2

In a similar manner to Example 1, the coupling reaction of the acid fromStep 1 of Example 23 (18.7 mg, 0.058 mmol) and4-(4-methyl-naphthalen-1-yl)-thiazol-2-ylamine (28 mg, 0.116 mmol)afforded the title compound of Example 23 as a white solid (13.8 mg, 44%yield). LC/MS (m/z 545.19 (M+H)⁺); HPLC Rt: 4.46 min

Example 24

To a solution of the title compound of Example 23 (11.8 mg, 0.217 mmol)in THF (1 ml) were added a solution of 40% KOH in water and 1 mlethanol. The reaction was stirred at room temperature for 4 hours. Thecrude product was filtered, and purified by prep HPLC to give the titlecompound of Example 24 as a white solid (10.8 mg, 100% yield). LC/MS(m/z 531.22 (M+H)⁺); HPLC Rt: 4.26 min.

1. A compound having the structure of formula (I):

or a stereoisomer thereof, or a tautomer thereof, or a pharmaceuticallyacceptable salt thereof, wherein R is hydrogen, NHR⁶, hydroxy, alkyl,alkenyl, alkynyl, alkoxy, aryl, arylalkyl, aryloxy, heteroaryl,cycloheteroalkyl, heteroarylalkyl, cycloheteroalkylalkyl, cycloalkyl,cycloalkylalkyl, cyanoalkyl, aminoalkyl, hydroxyalkyl, aryloxyalkyl, orhydroxyaryl; R⁴ and R⁵ are independently at each occurence hydroxy,alkoxy, aryloxy, cyano, nitro, NR^(e)R^(f), CHO, —CO₂alkyl,OCONR^(e)R^(f), OCO_(t)R^(e), OCO_(t)-aryl, OCO_(t)-heteroaryl,CONR^(e)R^(f), CH₂NR^(e)R^(f), CO₂H, OCSO_(t)R^(e)R^(f), CSNR^(e)R^(f),NR^(g)CO_(t)R^(i), NR^(g)CONR^(e)R^(f), NR^(g)CSNR^(e)R^(f),NR^(g)SO_(t)R^(i), NR^(g)SO₂R^(i), SO₂NR^(e)R^(f), orNR^(g)SO₂NR^(e)R^(f); R⁶ is hydrogen, S(O)_(t)R^(h), or C(O)_(t)R^(h);R^(a) and R^(b) are independently selected from hydrogen, halogen,hydroxy, alkyl, alkenyl, alkynyl, alkoxy, aryl, aryloxy, heteroaryl,cycloheteroalkyl, heteroarylalkyl, cycloheteroalkylalkyl, cyano,heteroarylaminocarboyl, cycloheteroalkylcarbonyl, cyanoalkyl,alkylaminoalkyl, hydroxyalkyl, hydroxyaryl, aryloxyalkyl, alkyloxyalkyl,nitro, NR^(e)R^(f), CHO, CO₂alkyl, CONR^(e)R^(f), CH₂NR^(e)R^(f), CO₂H,CH₂OH, CH₂NR^(e)R^(f), NHCOR^(g), NHCONR^(e)R^(f) and NHSO₂R^(g); R^(c)and R^(d) are independently selected from hydrogen, alkyl, alkenyl,alkynyl, alkoxy, NR^(e)R^(f), aryl, hydroxy, aryloxy, heteroaryl,cycloheteroalkyl, heteroarylalkyl, cycloheteroalkylalkyl, hydroxyaryl,and aryloxyalkyl; R^(e) and R^(f) are independently at each occurrenceselected from hydrogen, aryl, alkyl, alkenyl, alkynyl, alkoxy, amino,substituted amino, alkoxyalkyl, alkylaminoalkyl, dialkylaminoalkyl,heteroaryl, cycloheteroalkyl, heteroarylalkyl, cycloheteroalkylalkyl,cycloalkyl, and cycloalkylalkyl, provided R^(e) and R^(f) are not bothalkoxy or amino; or R^(e) and R^(f) at each occurrence can be takentogether with the nitrogen to which they are attached to form a 5-, 6-or 7-membered heteroaryl or cycloheteroalkyl ring which contains 1, 2 or3 hetero atoms which can be N, O or S; R^(g), R^(h) and R^(i) areindependently at each occurrence selected from hydrogen, aryl, alkyl,alkenyl, alkynyl, alkoxy, amino, substituted amino, alkoxyalkyl,alkylaminoalkyl, dialkylaminoalkyl, heteroaryl, cycloheteroalkyl,heteroarylalkyl, cycloheteroalkylalkyl, and cycloalkyl andcycloalkylalkyl; Z is S(O)_(t)NR¹R², CONR¹R² or CH₂NR¹R² wherein R¹ andR² are independently selected from hydrogen, alkyl, alkenyl, alkynyl,alkoxy, cycloalkyl, cycloalkylalkyl, aryl, heteroaryl, heteroarylalkyl,cycloheteroalkyl, cycloalkenyl, monoalkylaminoalkyl, dialkylaminoalkyl,cycloheteroalkylalkyl, hydroxyaryl, aryloxyalkyl, alkoxyalkyl andhydroxyalkyl; r and s are independently 0, 1, 2, 3, or 4, provided r+sis ≧1; and t is 1 or 2;
 2. A compound as defined in claim 1 or astereoisomer thereof, or a tautomer thereof, or a pharmaceuticallyacceptable salt thereof, wherein Z is a heterocycloalkyl, aryl, orheteroaryl ring.
 3. A compound as defined in claim 1, or a stereoisomerthereof, or a tautomer thereof, or a pharmaceutically acceptable saltthereof, where R is alkyl or NHR⁶; R^(a) and R^(b) are independentlyselected from hydrogen, halogen, alkyl, cyano, nitro, amino, formyl,CO₂alkyl, CONR^(e)R^(f) and CH₂NR^(e)R^(f); and R^(c) and R^(d) areindependently hydrogen, hydroxy, or nitro.
 4. A compound as defined inclaim 1 having the structure of formula (II)

or a stereoisomer thereof, or a tautomer thereof, or a pharmaceuticallyacceptable salt thereof, wherein R is NH₂, —NHC(O)C₁₋₄alkyl, orC₁₋₄alkyl; R^(a) and R^(b) are independently selected from hydrogen,halogen, C₁₋₄alkyl, cyano, nitro, amino, formyl, CO₂alkyl,CONR^(e)R^(f), and CH₂NR^(g)R^(h); R^(c) and R^(d) are independently Hor OH; and one of R¹ and R² is heteroaryl.
 5. A compound as defined inclaim 4, or a stereoisomer thereof, or a tautomer thereof, or apharmaceutically acceptable salt thereof, wherein R² is selected from:

R^(a) and R^(b) are independently H, C₁₋₄alkyl, Br, Cl, NO₂, CN, CHO, orNH₂; R^(m) and R^(n) are independently selected from hydrogen, halogen,alkoxy, —CO²R^(g)—C(O)N(R^(e))(R^(f)), alkyl, aryl, and heteroaryl;R^(o) is hydrogen or alkyl; and q is 1 or
 2. 6. A compound as defined inclaim 1, or a stereoisomer thereof, or a tautomer thereof, or apharmaceutically acceptable salt thereof, wherein R⁴ and R⁵ areindependently selected from cyano, nitro, CH₂NH₂, CHO, COOH, CO₂alkyl,OCOR^(e), OCO_(t)R^(f), CONR^(e)R^(f), and NR^(g)CO_(t)R^(i).
 7. Acompound as defined in claim 1 having the structure:

or a stereoisomer thereof, or a tautomer thereof, or a pharmaceuticallyacceptable salt thereof, wherein: R² is selected from

R⁴ and R⁵ are independently selected from cyano, nitro, CH₂NH₂, CHO,COOH, CO₂alkyl, OCOR^(e), OCO_(t)R^(f), CONR^(e)R^(f), andNR^(g)CO_(t)R^(i); and R^(a) and R^(b) are independently hydrogen,methyl, bromo, chloro, nitro, or cyano.
 8. A compound as defined inclaim 7, or a stereoisomer thereof, or a tautomer thereof, or apharmaceutically acceptable salt thereof, wherein: R^(m) is selectedfrom hydrogen, CO₂alkyl, napthyl, quinolinyl, or —C(R⁷)(R⁸)-T whereinthe napthyl or quinolinyl group is substituted by one or moresubstituents selected from the group consisting of hydrogen, amino,hydroxy, C₁₋₄ alkyl, C₁₋₄ alkoxy, perfluoro substituted C₁₋₄ alkyl,cyano, nitro and halogen; R^(n) is hydrogen, bromo, or chloro; T is acycloalkyl, cycloalkenyl, heterocycloalkyl, aryl, or heteroaryl ringwhere each ring is substituted by 0-4 R⁹ and 0-1 R¹⁰; R⁷ and R⁸ areindependently at each occurrence hydrogen, halogen, hydroxy, alkyl,alkenyl, alkynyl, alkoxy, cyano, nitro, NR^(e)R^(f), or CHO; or R⁷ andR⁸ combine to form ═O or a double bond, wherein the double bond issubstituted by hydrogen, aryl, alkyl, alkenyl, alkynyl, alkoxy, amino,substituted amino, alkoxyalkyl, alkylaminoalkyl, dialkylaminoalkyl,heteroaryl, cycloheteroalkyl, heteroarylalkyl, cycloheteroalkylalkyl,cycloalkyl, or cycloalkylalkyl; and R⁹ and R¹⁰ are, independently ateach occurrence, hydrogen, halogen, hydroxy, alkyl, alkenyl, alkynyl,alkoxy, aryl, aryloxy, heteroaryl, cycloheteroalkyl, heteroarylalkyl,cycloheteroalkylalkyl, cyano, heteroarylaminocarboyl,cycloheteroalkylcarbonyl, cyanoalkyl, alkylaminoalkyl, hydroxyalkyl,hydroxyaryl, aryloxyalkyl, alkoxyalkyl, nitro, oxo, NR^(e)R^(f), CHO,CO₂alkyl, CONR^(e)R^(f), CH₂NR^(e)R^(f), CO₂H, CH₂OH, CH₂NHC(O)R^(e),NHCOR^(i), NHCONR^(e)R^(f), NHSO_(p)R^(i), —SO₂NR^(e)R^(f),NR^(g)SO₂NR^(e)R^(f), or NR^(g)SO_(p)R^(i); or R⁹ and R¹⁰ located onadjacent atoms can be taken together to form an optionally substitutedcycloalkyl, aryl, heteroaryl, or cycloheteroalkyl ring.
 9. A compound asdefined in claim 8, or a stereoisomer thereof, or a tautomer thereof, ora pharmaceutically acceptable salt thereof, wherein: R^(n) is H; R^(m)is

R⁷ and R⁸ are independently hydrogen, halogen, or hydroxy; or R⁷ and R⁸combine to form ═O; and R⁹ is C₁₋₄alkoxy; halogen, pyrimidine,isoxazole, pyrazole, or pyridine, where the C₁₋₄alkoxy; halogen,pyrimidine, isoxazole, pyrazole, or pyridine, groups are substituted byhydrogen, morpholinyl, C₁₋₄alkoxy, or C₁₋₄alkyl.
 10. A compound asdefined in claim 8, or a stereoisomer thereof, or a tautomer thereof, ora pharmaceutically acceptable salt thereof, wherein: R^(n) is H; R^(m)is

or CO₂C₁₋₄alkyl; and R¹⁰ is selected from methyl, CF₃, fluoro, chloroand bromo.
 11. A compound as defined in claim 7 having the structure:

(ii) or a stereoisomer of (i) thereof, or a tautomer of (i) thereof, ora pharmaceutically acceptable salt of (i) thereof.
 12. A compound asdefined in claim 11, its stereoisomers thereof, tautomers thereof, or apharmaceutically acceptable salt thereof, wherein R⁴ is selected fromCONH₂, cyano, CH₂NH₂, CO₂CH₃, and COOH.
 13. A compound selected from:

(ii) a stereoisomer of of (i) thereof, or a tautomer of (i) thereof, ora pharmaceutically acceptable salt of (i) thereof.
 14. A method oftreating a disease which is associated with the expression product of agene whose transcription is stimulated or repressed by glucocorticoidreceptors, or a method of treating a disease associated with AP-1-and/or NF-κB-induced transcription, or a method for preventing,inhibiting onset of or treating a disease or disorder associated withAP-1 and/or N-κB dependent gene expression, wherein the disease isassociated with the expression of a gene under the regulatory control ofAP-1 and/or NF-κB, the method comprises administering to a patient inneed of treatment a therapeutically effective amount of a compound asdefined in claim
 1. 15. A method as defined in claim 14 wherein thedisease or disorder is selected from an endocrine disorder, rheumaticdisorder, collagen disease, dermatologic disease, allergic disease,ophthalmic disease, respiratory disease, hematologic disease,gastrointestinal disease, inflammatory disease, immune disease,neoplastic disease and metabolic disease.
 16. A method as defined inclaim 15 wherein the disease or disorder is an inflammatory orautoimmune disease wherein the disease or disorder is selected fromtransplant rejection of kidney, liver, heart, lung, pancreas, bonemarrow, cornea, small bowel, skin allografts, skin homografts, heartvalve xenograft, serum sickness, and graft vs. host disease, rheumatoidarthritis, psoriatic arthritis, multiple sclerosis, Type I and Type IIdiabetes, juvenile diabetes, obesity, asthma, inflammatory boweldisease, Crohn's disease, ulcerative colitis, pyoderma gangrenum,systemic lupus erythematosis, myasthenia gravis, psoriasis, dermatitis,dermatomyositis; eczema, seborrhoea, pulmonary inflammation, eyeuveitis, hepatitis, Grave's disease, Hashimoto's thyroiditis, autoimmunethyroiditis, Behcet's or Sjorgen's syndrome, pernicious orimmunohaemolytic anaemia, atherosclerosis, Addison's disease, idiopathicadrenal insufficiency, autoimmune polyglandular disease,glomerulonephritis, scleroderma, morphea, lichen planus, viteligo,alopecia areata, autoimmune alopecia, autoimmune hypopituatarism,Guillain-Barre syndrome, and alveolitis; contact hypersensitivity,delayed-type hypersensitivity, contact dermatitis, uticaria, skinallergies, respiratory allergies, hayfever, allergic rhinitis andgluten-sensitive enteropathy, osteoarthritis, acute pancreatis, chronicpancreatitis, acute respiratory distress syndrome, Sezary's syndrome,restenosis, stenosis and artherosclerosis, congenital adrenalhyperplasia, nonsuppurative thyroiditis, hypercalcemia associated withcancer, juvenile rheumatoid arthritis, Ankylosing spondylitis, acute andsubacute bursitis, acute nonspecific tenosynovitis, acute goutyarthritis, post-traumatic osteroarthritis, synovitis of osteoarthritis,epicondylitis, acute rheumatic carditis, pemphigus, bullous dermatitisherpetitformis, severe erythema multiforme, exfoliative dermatitis,psoriasis, seborrheic dermatitis, seasonal or perennial allergicrhinitis, bronchial asthma, contact dermatitis, atopic dermatitis, drughypersensitivity reactions, allergic conjuncivitis, keratitis, herpeszoster ophthalmicus, iritis and iridocyclitis, chorioretinitis, opticneuritis, symptomatic sarcoidosis, fulminating or disseminated pulmonarytuberculosis chemotherapy, idiopathic thrombocytopenic purpura inadults, secondary thrombocytopenia in adults, acquired (autoimmune)hemolytic anemia, leukemias and lymphomas in adults, acute leukemia ofchildhood, ulcerative colitis, regional enteritis, Crohn's disease,Sjogren's syndrome, autoimmune vasculitis, multiple sclerosis,myasthenia gravis, sepsis, and chronic obstructive pulmonary disease.17. The method as defined in claim 16 wherein the disease or disorder isselected from transplant rejection, rheumatoid arthritis, psoriaticarthritis, multiple sclerosis, Type I diabetes, asthma, inflammatorybowel disease, systemic lupus erythematosis, psoriasis and chronicpulmonary disease.
 18. A pharmaceutical composition comprising acompound as defined in claim 1 and a pharmaceutically acceptable carriertherefor.
 19. A pharmaceutical combination comprising a compound asdefined in claim 1 and an immunosuppressant, an anticancer agent, ananti-viral agent, an anti-inflammatory agent, an anti-fungal agent, ananti-biotic, an anti-vascular hyperproliferation agent, ananti-depressant agent, a lipid-lowering agent, a lipid modulating agent,an antidiabetic agent, an anti-obesity agent, an antihypertensive agent,a platelet aggregation inhibitor, and/or an antiosteoporosis agent,wherein the antidiabetic agent is 1, 2, 3 or more of a biguanide, asulfonyl urea, a glucosidase inhibitor, a PPAR γ agonist, a PPAR α/γdual agonist, an SGLT2 inhibitor, a DP4 inhibitor, an aP2 inhibitor, aninsulin sensitizer, a glucagon-like peptide-1 (GLP-1), insulin and/or ameglitinide, wherein the anti-obesity agent is a beta 3 adrenergicagonist, a lipase inhibitor, a serotonin (and dopamine) reuptakeinhibitor, a thyroid receptor agonist, an aP2 inhibitor and/or ananorectic agent, wherein the lipid lowering agent is an MTP inhibitor,an HMG CoA reductase inhibitor, a squalene synthetase inhibitor, afibric acid derivative, an upregulator of LDL receptor activity, alipoxygenase inhibitor, or an ACAT inhibitor, wherein theantihypertensive agent is an ACE inhibitor, angiotensin II receptorantagonist, NEP/ACE inhibitor, calcium channel blocker and/orβ-adrenergic blocker.
 20. The combination as defined in claim 19 whereinthe antidiabetic agent is 1, 2, 3 or more of metformin, glyburide,glimepiride, glipyride, glipizide, chlorpropamide, gliclazide, acarbose,miglitol, pioglitazone, troglitazone, rosiglitazone, insulin, G1-262570,isaglitazone, JTT-501, NN-2344, L895645, YM-440, R-119702, AJ9677,repaglinide, nateglinide, KAD1129, AR-HO39242, GW-409544, KRP297,AC2993, LY315902, P32/98 and/or NVP-DPP-728A, wherein the anti-obesityagent is orlistat, ATL-962, AJ9677, L750355, CP331648, sibutramine,topiramate, axokine, dexamphetamine, phentermine, phenylpropanolamine,and/or mazindol, wherein the lipid_lowering agent is pravastatin,lovastatin, simvastatin, atorvastatin, cerivastatin, fluvastatin,itavastatin, visastatin, fenofibrate, gemfibrozil, clofibrate,avasimibe, TS-962, MD-700, cholestagel, niacin and/or LY295427, whereinthe antihypertensive agent is an ACE inhibitor which is captopril,fosinopril, enalapril, lisinopril, quinapril, benazepril, fentiapril,ramipril or moexipril; an NEP/ACE inhibitor which is omapatrilat,[S[(R*,R*)]-hexahydro-6-[(2-mercapto-1-oxo-3-phenylpropyl)amino]-2,2-dimethyl-7-oxo-1H-azepine-1-aceticacid (gemopatrilat) or CGS 30440; an angiotensin II receptor antagonistwhich is irbesartan, losartan or valsartan; amlodipine besylate,prazosin HCl, verapamil, nifedipine, nadolol, propranolol, carvedilol,or clonidine HCl, wherein the platelet aggregation inhibitor is aspirin,clopidogrel, ticlopidine, dipyridamole or ifetroban; theimmunosuppressant is a cyclosporin, mycophenolate, interferon-beta,deoxyspergolin, FK-506 or Ant.-IL-2; the anti-cancer agent isazathiprine, 5-fluorouracel, cyclophosphamide, cisplatin, methotrexate,thiotepa, or carboplatin; the anti-viral agent is abacavir, aciclovir,ganciclovir, zidanocin, or vidarabine; and the antiinflammatory drug isibuprofen, celecoxib, rofecoxib, aspirin, naproxen, ketoprofen,diclofenac sodium, indomethacin, piroxicam, prednisone, dexamethasone,hydrocortisone, or triamcinolone diacetate.